Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: GO:0006457 "protein folding" is a well-supported core function of PFDN1. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from yeast GimC/prefoldin (SGD:S000003715), Arabidopsis, and human PFDN1 itself. The prefoldin complex is a bona fide co-chaperone that captures unfolded nascent polypeptides (primarily actin and tubulin) and delivers them to TRiC/CCT for ATP-dependent folding (PMID:9630229). Gestaut et al. 2019 (PMID:30955883) showed that PFD enhances the rate and yield of TRiC-mediated folding, directly demonstrating involvement in protein folding. The Reactome pathway R-HSA-389957 "Prefoldin mediated transfer of substrate to CCT/TriC" also supports this annotation. This is the central biological process for PFDN1. Reason: Protein folding is the core biological process for all prefoldin subunits. The IBA annotation is phylogenetically well-supported and consistent with the extensive experimental literature demonstrating prefoldin's role in delivering substrates to TRiC/CCT for folding (PMID:9630229, PMID:30955883). Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. PMID:30955883 PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles.
GO:0051082 unfolded protein binding	IBA GO_REF:0000033	MODIFY	Summary: GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962). This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from yeast (SGD:S000003715) and human PFDN1 itself. While prefoldin does indeed bind unfolded proteins, the term "unfolded protein binding" is a pure binding term that fails to capture the functional significance of this interaction. Prefoldin acts as a holdase/transfer chaperone: it captures unfolded substrates (primarily actin and tubulin) and delivers them to the TRiC/CCT chaperonin for folding. As described in Vainberg et al. 1998 (PMID:9630229), "Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it." The more appropriate term is GO:0044183 "protein folding chaperone" which captures the functional chaperone activity rather than just substrate binding. Notably, PFDN1 already has an IBA annotation to GO:0044183 in this same annotation set. Reason: GO:0051082 is being obsoleted. The term describes only a binding activity and does not capture the chaperone function of prefoldin. Prefoldin is a molecular chaperone that binds unfolded substrates and delivers them to TRiC/CCT for folding (PMID:9630229, PMID:30955883). GO:0044183 "protein folding chaperone" (defined as "Binding to a protein or a protein-containing complex to assist the protein folding process") is the recommended replacement and already exists as a separate IBA annotation for this gene. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. PMID:30955883 PFD alternates between an open "latched" conformation and a closed "engaged" conformation that aligns the PFD-TRiC substrate binding chambers.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: GO:0005737 "cytoplasm" is an appropriate cellular component annotation for PFDN1. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from C. elegans (WB:WBGene00007443). The prefoldin complex is a cytoplasmic chaperone that operates in the cytosol to capture unfolded nascent polypeptides and deliver them to the cytosolic chaperonin TRiC/CCT (PMID:9630229). The UniProt GO cross-references list this annotation, and the GOA qualifier "is_active_in" confirms that PFDN1 is active in the cytoplasm. Liang et al. 2020 (PMID:32699605) describe prefoldin as "a cytoplasmic chaperone protein." The term "cytoplasm" is appropriately broad, as a more specific CC annotation to "prefoldin complex" (GO:0016272) is already present in this annotation set. Having both is correct: one describes the subcellular location and the other describes the complex membership. Reason: PFDN1 operates as part of the cytoplasmic prefoldin complex. The cytoplasm annotation is well-supported and appropriately broad, complementing the more specific prefoldin complex (GO:0016272) annotation. The IBA phylogenetic inference is sound (PMID:9630229, PMID:32699605). Supporting Evidence: PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. PMID:32699605 As a cytoplasmic chaperone protein, the prefoldin complex is a hybrid oligomer assembled from six different proteins (six subunits).
GO:0044183 protein folding chaperone	IBA GO_REF:0000033	ACCEPT	Summary: GO:0044183 "protein folding chaperone" (defined as "Binding to a protein or a protein-containing complex to assist the protein folding process") is the most appropriate molecular function term for PFDN1. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from human PFDN1 itself. Prefoldin functions as a holdase/transfer chaperone that captures unfolded nascent polypeptides and delivers them to TRiC/CCT for folding (PMID:9630229). Gestaut et al. 2019 (PMID:30955883) demonstrated that the PFD-TRiC supra-chaperone assembly enhances folding rates and suppresses non-productive reaction cycles. This term precisely captures the functional role of PFDN1 as a co-chaperone that assists in protein folding, and is also the recommended replacement for the obsoleting GO:0051082 "unfolded protein binding." Reason: This is the core molecular function of PFDN1. The prefoldin complex is a bona fide protein folding chaperone that captures unfolded substrates and delivers them to TRiC/CCT (PMID:9630229, PMID:30955883). The IBA annotation is phylogenetically well-supported and represents the best available MF term for prefoldin subunits. Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. PMID:30955883 PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: GO:0006457 "protein folding" inferred electronically from InterPro domain mapping (IPR002777, the prefoldin beta-like domain). This IEA annotation is consistent with the IBA and IDA annotations to the same term, and with the well-established role of the prefoldin complex in protein folding (PMID:9630229). The InterPro-to-GO mapping is appropriate for this domain. Reason: The IEA annotation to protein folding via InterPro is correct and consistent with the higher-confidence IBA and IDA annotations. The prefoldin beta-like domain (IPR002777) is specifically associated with the protein folding function of the prefoldin complex (PMID:9630229, PMID:30955883).
GO:0016272 prefoldin complex	IEA GO_REF:0000002	ACCEPT	Summary: GO:0016272 "prefoldin complex" inferred electronically from InterPro domain mapping (IPR002777, the prefoldin beta-like domain). PFDN1 is one of the four beta subunits (PFDN1, PFDN2, PFDN4, PFDN6) of the heterohexameric prefoldin complex (PMID:9630229, PMID:32699605). The complex is also registered in ComplexPortal as CPX-6149 and CPX-25767. This IEA annotation is consistent with the IDA annotations to the same term from PMID:30955883 and PMID:23614719. Reason: PFDN1 is a core structural subunit of the prefoldin complex. The IEA mapping from the prefoldin beta-like domain (IPR002777) to prefoldin complex membership is appropriate and consistent with experimental evidence (PMID:9630229, PMID:30955883).
GO:0032991 protein-containing complex	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: GO:0032991 "protein-containing complex" was inferred electronically by the ARBA machine learning model (ARBA:ARBA00028902). While technically correct -- PFDN1 is part of the prefoldin complex, which is indeed a protein-containing complex -- this annotation is redundant and overly general given the more specific GO:0016272 "prefoldin complex" annotation that is already present in this annotation set from both IEA (InterPro) and IDA (PMID:30955883, PMID:23614719) evidence. The term "protein-containing complex" adds no informational value beyond what is already captured. Reason: This is an overly general annotation. PFDN1 is part of the prefoldin complex (GO:0016272), which is a child term of protein-containing complex. The more specific term is already annotated with both IEA and IDA evidence. The generic "protein-containing complex" adds no useful information.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962). This IEA annotation was inferred electronically from InterPro domain mapping (IPR002777, the prefoldin beta-like domain). The InterPro-to-GO mapping associates the prefoldin domain with unfolded protein binding, which is functionally accurate in that prefoldin subunits do contact unfolded substrates. However, since the term is being obsoleted, the annotation should be replaced with GO:0044183 "protein folding chaperone" which better describes the functional role of the prefoldin complex as a holdase/transfer chaperone that delivers substrates to TRiC/CCT. As noted by Liang et al. 2020 (PMID:32699605), "The prefoldin complex helps protein fold correctly and prevents aggregation by providing class II chaperones ... with a linear, unnatural substrate in the cytoplasm." Reason: GO:0051082 is being obsoleted. While the InterPro mapping correctly identifies that the prefoldin domain binds unfolded proteins, the replacement term GO:0044183 "protein folding chaperone" better captures the functional role of prefoldin as a chaperone that assists in protein folding by delivering unfolded substrates to the TRiC/CCT chaperonin (PMID:32699605, PMID:9630229). Proposed replacements: protein folding chaperone Supporting Evidence: PMID:32699605 The prefoldin complex helps protein fold correctly and prevents aggregation by providing class II chaperones (Hsp60 molecular chaperones found in archaebacteria and eukaryotic cytoplasm) with a linear, unnatural substrate in the cytoplasm [2] PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9Y2X7/GIT1) from Stelzl et al. 2005 (PMID:16169070), a large-scale yeast two-hybrid screen of the human proteome. The interaction between PFDN1 and GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) was identified in this high-throughput screen. GIT1 is involved in cell signaling and cytoskeletal organization. While this could represent a biologically relevant interaction (GIT1 is involved in cytoskeletal remodeling, and prefoldin assists in actin/tubulin folding), the "protein binding" term is uninformative. However, the interaction itself is from a large-scale screen and may not reflect a direct functional relationship. Reason: "Protein binding" is an uninformative term that does not describe any specific molecular function. The interaction with GIT1 (Q9Y2X7) was detected in a high-throughput Y2H screen (PMID:16169070), and while the interaction may be real, the GO term provides no functional insight. More informative annotations such as GO:0044183 "protein folding chaperone" already capture the core binding function of PFDN1.
GO:0005515 protein binding	IPI PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2) from Tsao et al. 2006 (PMID:16876117). This study used yeast two-hybrid and co-immunoprecipitation to demonstrate that HCV F protein interacts with PFDN2, and that HCV F protein "impeded the interaction between prefoldin 1 and 2." This confirms the PFDN1-PFDN2 interaction, which is expected since they are both subunits of the same heterohexameric prefoldin complex. The UniProt record confirms this interaction (NbExp=6). However, "protein binding" is uninformative -- this interaction reflects prefoldin complex assembly rather than a generic binding function. The annotation is not wrong but the term is too vague to be useful. Reason: "Protein binding" is uninformative. The PFDN1-PFDN2 interaction reflects subunit assembly within the prefoldin complex and is already captured by the GO:0016272 "prefoldin complex" CC annotation. The PMID:16876117 study was primarily about HCV F protein interaction with PFDN2, not PFDN1 function. Supporting Evidence: PMID:16876117 In the yeast three-hybrid system, it was found that expression of HCV F protein impeded the interaction between prefoldin 1 and 2.
GO:0005515 protein binding	IPI PMID:21900206 A directed protein interaction network for investigating int...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9Y2X7/GIT1) from Vinayagam et al. 2011 (PMID:21900206), a directed protein interaction network study. This is a second independent detection of the PFDN1-GIT1 interaction (also seen in PMID:16169070). While the replication adds some confidence that the interaction is real, "protein binding" remains uninformative as a GO annotation for PFDN1. The biological significance of a PFDN1-GIT1 interaction is unclear. Reason: "Protein binding" is uninformative. This high-throughput interaction screen detection of PFDN1-GIT1 binding does not provide functional insight. The core molecular function of PFDN1 is already captured by GO:0044183 "protein folding chaperone."
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2) from Huttlin et al. 2017 (PMID:28514442), the BioPlex human interactome study. This is another independent detection of the PFDN1-PFDN2 intra-complex interaction, which is expected for subunits of the same hexameric complex. The "protein binding" term is uninformative and the interaction is already captured by the prefoldin complex membership annotation (GO:0016272). Reason: "Protein binding" is uninformative. The PFDN1-PFDN2 interaction reflects co-membership in the prefoldin complex, already captured by GO:0016272. This high-throughput interactome study provides no additional functional insight beyond complex membership.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9NPF5/DMAP1) from Luck et al. 2020 (PMID:32296183), a reference map of the human binary protein interactome (HuRI). DMAP1 (DNA methyltransferase 1-associated protein 1) is a component of NuA4/TIP60 histone acetyltransferase complex. The UniProt record for PFDN1 lists this interaction (NbExp=3). While the interaction may be real, its biological significance for PFDN1 function is unclear. DMAP1 is a nuclear protein whereas PFDN1 functions primarily in the cytoplasm. The "protein binding" term is uninformative. Reason: "Protein binding" is uninformative. The PFDN1-DMAP1 interaction was detected in a high-throughput binary interactome screen. The biological relevance is unclear given that PFDN1 is cytoplasmic and DMAP1 is nuclear. The core molecular function of PFDN1 is already captured by GO:0044183.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2 and UniProtKB:Q9Y2X7/GIT1) from Huttlin et al. 2021 (PMID:33961781), a dual proteome-scale network study of the human interactome. This confirms previously observed interactions: the PFDN1-PFDN2 interaction (intra-complex) and the PFDN1-GIT1 interaction. Both interactions have been detected in multiple independent studies. However, "protein binding" remains uninformative as a functional annotation. Reason: "Protein binding" is uninformative. These are replications of previously observed interactions (PFDN1-PFDN2 intra-complex; PFDN1-GIT1) that do not add functional insight beyond what is captured by GO:0016272 (prefoldin complex) and GO:0044183 (protein folding chaperone).
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2 and UniProtKB:Q9Y2X7/GIT1) from multimodal cell maps study (PMID:40205054). This is yet another replication of the PFDN1-PFDN2 and PFDN1-GIT1 interactions. The PFDN1-PFDN2 interaction is expected as both are subunits of the prefoldin complex. The "protein binding" term remains uninformative. Reason: "Protein binding" is uninformative. This is a further replication of known interactions (PFDN1-PFDN2, PFDN1-GIT1) from a large-scale study. The relevant functions are already captured by more specific annotations (GO:0044183, GO:0016272).
GO:0006457 protein folding	NAS PMID:32699605 The functions and mechanisms of prefoldin complex and prefol...	ACCEPT	Summary: GO:0006457 "protein folding" (NAS) from ComplexPortal, citing Liang et al. 2020 (PMID:32699605), a comprehensive review of prefoldin complex functions. The review describes how "the prefoldin complex helps protein fold correctly and prevents aggregation by providing class II chaperones ... with a linear, unnatural substrate in the cytoplasm." This NAS annotation is consistent with the IBA and IDA annotations to the same term and is well-supported by the review literature. Reason: Protein folding is the core biological process for PFDN1. This NAS annotation from ComplexPortal cites a well-sourced review (PMID:32699605) that accurately describes the protein folding function of the prefoldin complex. Consistent with IBA and IDA evidence to the same term. Supporting Evidence: PMID:32699605 The prefoldin complex helps protein fold correctly and prevents aggregation by providing class II chaperones (Hsp60 molecular chaperones found in archaebacteria and eukaryotic cytoplasm) with a linear, unnatural substrate in the cytoplasm [2]
GO:0006457 protein folding	NAS PMID:34761191 A comprehensive analysis of prefoldins and their implication...	ACCEPT	Summary: GO:0006457 "protein folding" (NAS) from ComplexPortal, citing Herranz-Montoya et al. 2021 (PMID:34761191), a comprehensive analysis of prefoldins and their implication in cancer. The review describes prefoldins as "evolutionary conserved co-chaperones" that "act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins." This NAS annotation is consistent with the IBA and IDA annotations to the same term and is well-supported. Reason: Protein folding is the core biological process for PFDN1. This NAS annotation from ComplexPortal cites a comprehensive review (PMID:34761191) that accurately describes the co-chaperone function of prefoldin subunits. Consistent with IBA and IDA evidence. Supporting Evidence: PMID:34761191 PFDNs are prevalently organized into hetero-hexameric complexes. Although they have been overlooked since their discovery and their functions remain elusive, several reports indicate they act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins.
GO:0050821 protein stabilization	NAS PMID:34761191 A comprehensive analysis of prefoldins and their implication...	KEEP AS NON CORE	Summary: GO:0050821 "protein stabilization" (NAS) from ComplexPortal, citing Herranz-Montoya et al. 2021 (PMID:34761191). The GO definition of protein stabilization is "Any process involved in maintaining the structure and integrity of a protein and preventing it from degradation or aggregation." Prefoldin does prevent aggregation of unfolded substrates by capturing them and delivering them to TRiC/CCT (PMID:9630229). However, "protein stabilization" typically implies maintaining a folded protein in its native state, whereas prefoldin acts on unfolded nascent polypeptides as a holdase and transfer chaperone. The term is not entirely wrong -- prefoldin does prevent aggregation -- but it mischaracterizes the nature of the chaperone activity. The more accurate process annotation is GO:0006457 "protein folding," which is already well-annotated. Reason: While prefoldin does prevent protein aggregation (which is part of the GO definition of protein stabilization), the primary function is not to stabilize already-folded proteins but rather to capture unfolded substrates and transfer them to TRiC/CCT for folding. The annotation is not wrong but represents a secondary aspect of prefoldin function rather than its core activity. The core process (protein folding, GO:0006457) is already well-annotated with IBA, IDA, and NAS evidence. Supporting Evidence: PMID:34761191 PFDNs are prevalently organized into hetero-hexameric complexes. Although they have been overlooked since their discovery and their functions remain elusive, several reports indicate they act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins.
GO:0006457 protein folding	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	ACCEPT	Summary: GO:0006457 "protein folding" (IDA) from Gestaut et al. 2019 (PMID:30955883), which used cryo-EM, crosslinking mass spectrometry, and biochemical reconstitution to characterize the structural and functional interplay between the prefoldin (PFD) complex and TRiC/CCT chaperonin. The study demonstrates that "PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles," directly showing involvement in protein folding. This is the highest-quality direct experimental evidence for the protein folding function of the prefoldin complex. Reason: This IDA annotation is supported by strong direct experimental evidence from Gestaut et al. 2019 (PMID:30955883), which demonstrated through cryo-EM and biochemical approaches that the PFD-TRiC supra-chaperone assembly enhances protein folding rates. Protein folding is the core biological process for PFDN1. Supporting Evidence: PMID:30955883 PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles. PMID:30955883 The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis.
GO:0016272 prefoldin complex	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	ACCEPT	Summary: GO:0016272 "prefoldin complex" (IDA) from Gestaut et al. 2019 (PMID:30955883). This study used reconstituted human prefoldin complex (containing all six subunits including PFDN1) and characterized its structure and function through cryo-EM, crosslinking mass spectrometry, and biochemical assays. The study resolved the architecture of the PFD-TRiC supra-chaperone complex, directly demonstrating that PFDN1 is a component of the prefoldin complex. The cryo-EM structures (PDB: 6NR8, 6NR9, 6NRB, 6NRC, 6NRD) include PFDN1 as a structural component. Reason: PFDN1 is a core structural subunit of the prefoldin complex. This IDA annotation is supported by high-resolution cryo-EM structural data from Gestaut et al. 2019 (PMID:30955883) that directly demonstrates PFDN1 as a component of the human prefoldin complex. Supporting Evidence: PMID:30955883 Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems. To understand how the essential ring-shaped chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry and biochemical and cellular approaches to elucidate the structural and functional interplay between TRiC/CCT and PFD.
GO:0051082 unfolded protein binding	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	MODIFY	Summary: GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962). This IDA annotation cites Gestaut et al. 2019 (PMID:30955883), which used cryo-EM, crosslinking mass spectrometry, and biochemical reconstitution to characterize the structural and functional interplay between the prefoldin (PFD) complex and TRiC/CCT chaperonin. The study demonstrates that prefoldin associates with TRiC through a conserved electrostatic interface and undergoes conformational cycling between "latched" (open) and "engaged" (closed) states during substrate transfer. Critically, the paper shows that PFD functions not merely as a passive binder of unfolded substrates but as an active co-chaperone that "can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles." This demonstrates prefoldin is a bona fide protein folding chaperone. GO:0044183 "protein folding chaperone" is the appropriate replacement, capturing the functional role of prefoldin in the chaperone-assisted folding pathway. Reason: GO:0051082 is being obsoleted. Gestaut et al. 2019 (PMID:30955883) demonstrates that prefoldin functions as a co-chaperone/holdase that cooperates with TRiC/CCT in substrate folding, not merely as an unfolded protein binder. The study shows prefoldin enhances the rate and yield of TRiC-mediated folding and that disrupting the PFD-TRiC interaction leads to accumulation of amyloid aggregates in vivo. GO:0044183 "protein folding chaperone" accurately describes this co-chaperone activity. Note that while prefoldin itself functions primarily as a holdase (it does not fold proteins on its own but transfers them to TRiC), the GO:0044183 definition ("Binding to a protein or a protein-containing complex to assist the protein folding process") appropriately encompasses this transfer/holdase function. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:30955883 PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles. PMID:30955883 Disrupting the TRiC-PFD interaction in vivo is strongly deleterious, leading to accumulation of amyloid aggregates. PMID:30955883 The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis. PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. ... prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins.
GO:0001540 amyloid-beta binding	IDA PMID:23614719 Human prefoldin inhibits amyloid-β (Aβ) fibrillation and con...	KEEP AS NON CORE	Summary: GO:0001540 "amyloid-beta binding" (IDA) from Sorgjerd et al. 2013 (PMID:23614719). This study demonstrated that recombinant human prefoldin (hPFD) inhibits amyloid-beta (Abeta 1-42) fibrillation in vitro and induces formation of soluble Abeta oligomers with reduced toxicity. The study used thioflavin T measurements and immunoblotting to show that hPFD directly interacts with Abeta peptides and modifies their aggregation pathway. While this demonstrates that the prefoldin complex can bind Abeta, this is not the core function of PFDN1 -- it reflects the general chaperone/holdase property of prefoldin applied to an amyloidogenic substrate. The annotation was made on the intact prefoldin complex, not PFDN1 individually. Reason: Amyloid-beta binding is a secondary, non-core function that reflects the general holdase/chaperone activity of the prefoldin complex applied to an amyloidogenic substrate. The study (PMID:23614719) used the intact hexameric complex rather than individual PFDN1. While the data are solid, this represents a peripheral function compared to the core role in actin/tubulin folding via TRiC/CCT delivery. Supporting Evidence: PMID:23614719 we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42) aggregation in vitro and found that hPFD inhibited Abeta fibrillation and induced formation of soluble Abeta oligomers.
GO:0016272 prefoldin complex	IDA PMID:23614719 Human prefoldin inhibits amyloid-β (Aβ) fibrillation and con...	ACCEPT	Summary: GO:0016272 "prefoldin complex" (IDA) from Sorgjerd et al. 2013 (PMID:23614719). This study expressed and purified recombinant human prefoldin complex (hPFD) to investigate its effect on amyloid-beta aggregation. The successful reconstitution and purification of the hexameric complex containing PFDN1 provides direct evidence for PFDN1 membership in the prefoldin complex. This is consistent with the IDA annotation from PMID:30955883 and the IEA annotation from InterPro. Reason: PFDN1 is a core structural subunit of the prefoldin complex. This IDA annotation from PMID:23614719 provides independent experimental evidence through reconstitution of the human prefoldin hexamer, consistent with the structural data from PMID:30955883. Supporting Evidence: PMID:23614719 Prefoldin (PFD) is a molecular chaperone that prevents aggregation of misfolded proteins.
GO:1905907 negative regulation of amyloid fibril formation	IDA PMID:23614719 Human prefoldin inhibits amyloid-β (Aβ) fibrillation and con...	KEEP AS NON CORE	Summary: GO:1905907 "negative regulation of amyloid fibril formation" (IDA) from Sorgjerd et al. 2013 (PMID:23614719). The study demonstrated that recombinant human prefoldin "inhibited Abeta fibrillation and induced formation of soluble Abeta oligomers" that were 30-40% less toxic than Abeta fibrils. Thioflavin T measurements confirmed reduced fibril formation. While the experimental evidence is sound, this represents a non-core function of the prefoldin complex -- an extension of its general holdase/chaperone properties to amyloidogenic substrates rather than its primary role in actin/tubulin folding. The study was performed on the intact hexameric complex, not PFDN1 individually. Reason: The experimental evidence from PMID:23614719 is solid, but this is a secondary function reflecting the general anti-aggregation properties of the prefoldin complex rather than its core role in delivering unfolded actin/tubulin to TRiC/CCT. The study was performed in vitro on the intact hexameric complex, and the relevance to PFDN1 specifically (as opposed to the complex as a whole) is indirect. Supporting Evidence: PMID:23614719 we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42) aggregation in vitro and found that hPFD inhibited Abeta fibrillation and induced formation of soluble Abeta oligomers. PMID:23614719 Our findings show a relation between cytotoxicity of Abeta oligomers and structure and suggest a possible protective role of PFD in AD.
GO:0044183 protein folding chaperone	IPI PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	ACCEPT	Summary: GO:0044183 "protein folding chaperone" (IPI with UniProtKB:Q9UHV9/PFDN2) from Tsao et al. 2006 (PMID:16876117), annotated by AgBase. This study demonstrated that HCV F protein interacts with PFDN2 and that this interaction "impeded the interaction between prefoldin 1 and 2," resulting in "aberrant organization of tubulin cytoskeleton." The study describes prefoldin as "a hexameric molecular chaperone complex ... which delivers nascent actin and tubulin proteins to the eukaryotic cytosolic chaperonin for facilitated folding." The IPI evidence code is appropriate because the chaperone function of PFDN1 was demonstrated through its interaction with PFDN2 in the context of prefoldin complex assembly and function. The study shows that disrupting the PFDN1-PFDN2 interaction (via HCV F protein) impairs the chaperone function of the complex, providing indirect evidence that PFDN1 enables protein folding chaperone activity through the complex. Reason: GO:0044183 "protein folding chaperone" is the core molecular function of PFDN1. This IPI annotation is supported by PMID:16876117, which demonstrates that PFDN1-PFDN2 interaction is essential for prefoldin complex assembly and chaperone function. Disruption of this interaction by HCV F protein leads to aberrant tubulin cytoskeleton, confirming the functional significance. Supporting Evidence: PMID:16876117 Prefoldin 2 is a subunit of a hexameric molecular chaperone complex, named prefoldin, which delivers nascent actin and tubulin proteins to the eukaryotic cytosolic chaperonin for facilitated folding. PMID:16876117 In the yeast three-hybrid system, it was found that expression of HCV F protein impeded the interaction between prefoldin 1 and 2.

Core Functions

PFDN1 is a beta-type subunit of the heterohexameric prefoldin co-chaperone complex that captures unfolded nascent polypeptides (primarily actin and tubulin) and delivers them to the TRiC/CCT chaperonin for ATP-dependent folding. The prefoldin-TRiC supra-chaperone assembly enhances the rate and yield of the folding reaction and suppresses non-productive reaction cycles (PMID:30955883). The client repertoire extends beyond cytoskeletal proteins to include the VHL tumor suppressor, where prefoldin prevents pVHL aggregation and degradation (DOI:10.1371/journal.pgen.1009183). A 2024 DIP-MS study resolved canonical and alternative prefoldin assemblies, suggesting context-specific modular complex organization (DOI:10.1038/s41592-024-02211-y).

Molecular Function:

protein folding chaperone

Directly Involved In:

protein folding

Cellular Locations:

cytoplasm

In Complex:

prefoldin complex

Supporting Evidence:

PMID:9630229
We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
PMID:30955883
PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:16169070

A human protein-protein interaction network: a resource for annotating the proteome.

PMID:16876117

Interaction of hepatitis C virus F protein with prefoldin 2 perturbs tubulin cytoskeleton organization.

PMID:21900206

A directed protein interaction network for investigating intracellular signal transduction.

PMID:23614719

Human prefoldin inhibits amyloid-β (Aβ) fibrillation and contributes to formation of nontoxic Aβ aggregates.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:30955883

The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic Interface Essential for Cellular Proteostasis.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32699605

The functions and mechanisms of prefoldin complex and prefoldin-subunits.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:34761191

A comprehensive analysis of prefoldins and their implication in cancer.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:9630229

Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin.

DOI:10.1371/journal.pgen.1009183

The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation

Prefoldin complex physically associates with pVHL in human cells and prefoldin knockdown reduces pVHL expression
In yeast, prefoldin mutants promote pVHL aggregation, supporting a role in client stabilization beyond actin and tubulin

DOI:10.1038/s41592-024-02211-y

DIP-MS ultra-deep interaction proteomics for the deconvolution of protein complexes

DIP-MS resolved canonical and alternative prefoldin assemblies in human cells, with PFDN1 as a component, supporting modular complex isoforms
Prefoldin subunits show coelution and association patterns linked to CCT/TRiC with n equals 3 biologically independent replicates

DOI:10.1038/onc.2016.257

Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin A expression

PFDN1 increases during TGF-beta1-induced EMT and localizes to the nucleus in cancer contexts
PFDN1 represses cyclin A expression by directly interacting with the cyclin A promoter near the transcription start site

DOI:10.1007/s12032-015-0710-z

PFDN1 an indicator for colorectal cancer prognosis enhances tumor cell proliferation and motility through cytoskeletal reorganization

PFDN1 knockdown reduces F-actin levels and alpha-tubulin staining in colorectal cancer cells, consistent with impaired cytoskeletal homeostasis
PFDN1 knockdown in xenografts reduced tumor weight to 346.8 mg versus 783.4 mg in controls (P less than 0.01)

DOI:10.3389/fcell.2021.816214

Prefoldin function in cellular protein homeostasis and human diseases

Review emphasizes canonical prefoldin function as transfer of cytoskeletal polypeptides to TRiC/CCT while highlighting non-canonical functions in transcription regulation and proteasome-dependent degradation

📚 Additional Documentation

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organism_full: Homo sapiens (Human).
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O60925
Protein Description: RecName: Full=Prefoldin subunit 1;
Gene Information: Name=PFDN1; Synonyms=PFD1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the prefoldin subunit beta family.
Key Domains: PFD_beta-like. (IPR002777); Prefoldin. (IPR009053); Prefoldin_2 (PF01920)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PFDN1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'PFDN1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene PFDN1 (gene ID: PFDN1, UniProt: O60925) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: O60925
Protein Description: RecName: Full=Prefoldin subunit 1;
Gene Information: Name=PFDN1; Synonyms=PFD1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the prefoldin subunit beta family.
Key Domains: PFD_beta-like. (IPR002777); Prefoldin. (IPR009053); Prefoldin_2 (PF01920)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PFDN1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene PFDN1 (gene ID: PFDN1, UniProt: O60925) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Title: Functional Annotation Research Report — Human PFDN1 (UniProt O60925; Prefoldin subunit 1)

Publication-date note: This report prioritizes 2023–2024 sources when available, but key mechanistic evidence for PFDN1 derives from earlier primary studies (2015–2021) that remain foundational. All major claims are supported by citations to retrieved full text.

Target verification (gene/protein identity)

The target is human PFDN1 (UniProt O60925), whose protein product is “Prefoldin subunit 1,” a β-type subunit of the canonical hetero-hexameric prefoldin (PFD) complex in eukaryotes (PFDN1–PFDN6). This is supported by human-cell experimental papers and systems-level proteomics mapping that explicitly list PFDN1 within canonical prefoldin assemblies and describe its cochaperone role with the cytosolic chaperonin CCT/TRiC. (chesnel2020theprefoldincomplex pages 18-19, chesnel2020theprefoldincomplex pages 1-2, fabian2024dipmsultradeepinteraction pages 7-8)

Key concepts and definitions (current understanding)

2.1 Canonical prefoldin and PFDN1’s molecular role

Prefoldin is a conserved hetero-hexameric cochaperone complex that binds non-native polypeptides, protects exposed hydrophobic regions to prevent aggregation, and transfers/shuttles folding clients to the cytosolic chaperonin TRiC/CCT for productive folding. PFDN1 is one of the canonical subunits of this complex and is repeatedly listed among prefoldin components in human-cell studies. (chesnel2020theprefoldincomplex pages 18-19, chesnel2020theprefoldincomplex pages 1-2, fabian2024dipmsultradeepinteraction pages 7-8)

A core, experimentally supported client class is cytoskeletal proteins: actin and tubulin monomers. In colorectal cancer cells, PFDN1 is described as enhancing the efficiency of actin and tubulin folding by returning partially folded substrates to CCT for additional folding cycles, consistent with a prefoldin–CCT functional relay. (wang2015pfdn1anindicator pages 9-10)

2.2 Prefoldin–CCT/TRiC coupling and complex membership evidence

Human-cell experiments link prefoldin to CCT/TRiC not just conceptually but via co-recovery/co-association in proteomic and interaction studies: in a pVHL folding/stability study, mass spectrometry from VHL pulldowns recovered multiple prefoldin subunits (including PFDN1) and CCT/TRiC subunits, consistent with a shared folding network around client proteins. (chesnel2020theprefoldincomplex pages 5-6, chesnel2020theprefoldincomplex pages 18-19)

A 2024 Nature Methods study that maps “prefoldin family complexes” provides systems-level evidence that canonical prefoldin subunits, including PFDN1, form a defined assembly and show association/coelution patterns linked to CCT/TRiC. (fabian2024dipmsultradeepinteraction pages 8-8, fabian2024dipmsultradeepinteraction pages 7-8)

2.3 Cellular localization: cytosol and non-canonical nuclear roles

Canonical prefoldin function is cytosolic in protein quality control and cytoskeletal biogenesis, but PFDN1 has also been reported to localize to the nucleus in cancer contexts and to exert transcriptional regulatory activity, indicating non-canonical nuclear functions beyond cytoskeletal folding. (wang2017prefoldin1promotes pages 1-2)

Functional biology of PFDN1 (processes, pathways, and mechanistic models)

3.1 Protein homeostasis and client stabilization: pVHL as an example client

Prefoldin can stabilize specific client proteins by preventing aggregation and assisting folding via CCT/TRiC. In the context of the von Hippel–Lindau tumor suppressor protein (pVHL), the prefoldin complex physically associates with pVHL in human cells, and prefoldin knockdown reduces pVHL expression; in yeast, prefoldin mutants promote pVHL aggregation. These findings support a role for prefoldin (and by implication PFDN1 as a subunit) in client stabilization and folding/quality control. (chesnel2020theprefoldincomplex pages 18-19, chesnel2020theprefoldincomplex pages 5-6)

3.2 Cytoskeletal reorganization and tumor cell phenotypes (CRC example)

In colorectal cancer models (SW480, RKO), PFDN1 knockdown produces less spread/aggressive morphology, reduces cytoskeletal structures (stress fibers), decreases F-actin levels, and weakens α-tubulin staining, consistent with impaired cytoskeletal homeostasis. (wang2015pfdn1anindicator pages 9-10)

Quantitatively, in nude-mouse xenografts derived from SW480 cells, stable PFDN1 knockdown markedly reduced tumor burden and proliferation: tumor weights were 346.8 ± 118.1 mg in shPFDN1 tumors versus 783.4 ± 163.8 mg (mock) and 737.2 ± 203.2 mg (NC), with reported P < 0.01; Ki-67 positive fraction was 38 ± 10% in shPFDN1 versus 65 ± 17% (mock) and 71 ± 12% (NC), with reported P < 0.05. (wang2015pfdn1anindicator pages 9-10)

3.3 EMT/metastasis pathways and transcriptional repression (lung cancer example)

In lung cancer, PFDN1 is reported to increase during TGF-β1-induced epithelial–mesenchymal transition (EMT), and nuclear localization of PFDN1 is detected. Mechanistically, PFDN1 can repress cyclin A expression by directly interacting with the cyclin A promoter near the transcription start site; cyclin A overexpression can abrogate PFDN1-driven EMT/invasion phenotypes, while cyclin A knockdown can phenocopy EMT-like changes. Together these data support a non-canonical nuclear transcriptional mechanism (TGF-β1/PFDN1/cyclin A axis) contributing to EMT and metastasis. (wang2017prefoldin1promotes pages 1-2)

3.4 Wnt/β-catenin pathway activation (gastric cancer example)

In gastric cancer, PFDN1 is reported as upregulated and associated with metastasis and poor prognosis; mechanistically, PFDN1 is described as promoting migration/invasion/metastasis by activating Wnt/β-catenin signaling with EMT marker changes. (zhou2020pfnd1predictspoor pages 1-2)

Recent developments and latest research (prioritize 2023–2024)

4.1 2024 systems-level prefoldin complex mapping by DIP-MS (Nature Methods)

A major 2024 advance is the introduction/application of DIP-MS (deep interactome profiling by mass spectrometry) to resolve organization of the “human prefoldin family of complexes.” This work reports that prefoldin assemblies include canonical subunits (including PFDN1) and reveals alternative assemblies/complex isoforms, supported by both DIP-MS and AP–MS strategies. Experiments are reported with n = 3 biologically independent replicates, and structural comparisons report similarity metrics (TM score > 45; TM scores reported as mean ± s.e.m.). (fabian2024dipmsultradeepinteraction pages 7-8)

The visual evidence (cropped figure regions) from this study shows canonical prefoldin composition including PFDN1 and coelution/association patterns involving prefoldin subunits and CCT/TRiC subunits. (fabian2024dipmsultradeepinteraction media 5b2ee584, fabian2024dipmsultradeepinteraction media 01045fb5)

Interpretation: These 2024 findings strengthen current understanding that PFDN1’s functional context is best described at the “prefoldin family complex” level rather than as a lone factor, and that prefoldin may exist in modular/alternative assemblies that could underlie context-specific functions.

URL / publication date: https://doi.org/10.1038/s41592-024-02211-y (published March 2024). (fabian2024dipmsultradeepinteraction pages 7-8)

4.2 2024 cancer dependency on a prefoldin-like complex (Molecular Cell)

A 2024 Molecular Cell study on medulloblastoma reports that a non-canonical ORF (ASNSD1-uORF/ASDURF) is required for cancer cell survival through engagement with a prefoldin-like chaperone complex, in which PFDN1 is shown as a member of prefoldin(-like) assemblies. The figure excerpt indicates CRISPR/sgRNA perturbation designs with n = 3 replicate annotations and multiple comparisons labeled with very strong significance (p < 0.0001) in proteomics-based analyses. (hofman2024translationofnoncanonical pages 57-57)

Interpretation: Although not a direct “PFDN1-only” mechanism, this supports a 2024 view that prefoldin(-like) assemblies (including PFDN1) can be rewired or co-opted by oncogenic programs and non-canonical translated ORFs.

URL / publication date: https://doi.org/10.1016/j.molcel.2023.12.003 (published January 2024). (hofman2024translationofnoncanonical pages 57-57)

Current applications and real-world implementations

5.1 Biomarker/prognostic indicator concepts

PFDN1 has been positioned as a prognostic indicator/biomarker candidate in multiple cancers in translational primary studies and reviews. In colorectal cancer, mechanistic evidence links PFDN1 to increased tumor growth and cytoskeletal-driven motility, consistent with its use as a prognosis-associated marker in that context. (wang2015pfdn1anindicator pages 9-10)

A review-level synthesis integrating TCGA and literature reports indicates PFDN1 mRNA is moderately but significantly increased in colorectal cancer (fold change 0.35; p < 5.0E-3), supporting a population-level expression shift consistent with biomarker exploration. (herranzmontoya2021acomprehensiveanalysis pages 18-20)

5.2 Experimental/technical implementations used in the field

Common experimental implementations for PFDN1 functional inference include:

• Genetic perturbation (siRNA/shRNA knockdown; overexpression) followed by phenotyping of proliferation, migration/invasion, and EMT marker changes. (wang2017prefoldin1promotes pages 1-2, wang2015pfdn1anindicator pages 9-10)

• In vivo xenografts in nude mice to quantify tumor growth/proliferation impacts of PFDN1 modulation (with Ki-67 IHC readouts). (wang2015pfdn1anindicator pages 9-10)

• Chromatin/promoter interaction assays supporting direct transcriptional repression (cyclin A promoter interaction by PFDN1). (wang2017prefoldin1promotes pages 1-2)

• Proteomics and interactome mapping (BioID/AP–MS; DIP-MS) to define complex membership and coupling to CCT/TRiC. (chesnel2020theprefoldincomplex pages 5-6, fabian2024dipmsultradeepinteraction pages 7-8)

Expert opinions and authoritative analysis (reviews)

A 2022 review on prefoldin in proteostasis and disease emphasizes canonical prefoldin function as transfer of cytoskeletal polypeptides to TRiC/CCT, while highlighting non-canonical functions (transcription regulation and proteasome-dependent degradation) and disease links including cancer. The review specifically cites PFDN1 contributions to cancer progression and metastasis via Wnt/β-catenin and via transcriptional suppression mechanisms (cyclin A axis). (tahmaz2022prefoldinfunctionin pages 8-9)

A 2021 iScience review provides an integrative analysis of prefoldins in cancer, including TCGA-derived expression statistics and a synthesis of functional phenotypes from PFDN1 perturbation in colorectal cancer. (herranzmontoya2021acomprehensiveanalysis pages 18-20)

Relevant statistics and data (selected, with context)

7.1 Quantitative tumor biology readouts (CRC xenograft)

PFDN1 knockdown reduced xenograft tumor weight and proliferation index as follows (SW480-derived tumors, day 25):

• Tumor weights: 346.8 ± 118.1 mg (shPFDN1) vs 783.4 ± 163.8 mg (mock) and 737.2 ± 203.2 mg (negative control), P < 0.01.

• Ki-67 index: 38 ± 10% (shPFDN1) vs 65 ± 17% and 71 ± 12%, P < 0.05.

These data link PFDN1 functionally to in vivo tumor proliferation and provide quantitative support for its role in CRC growth. (wang2015pfdn1anindicator pages 9-10)

7.2 Population-scale expression statistics (TCGA-derived CRC mRNA increase)

A TCGA analysis summarized in an iScience review reports PFDN1 mRNA is significantly increased in colorectal cancer compared with adjacent tissue (fold change 0.35; p < 5.0E-3). (herranzmontoya2021acomprehensiveanalysis pages 18-20)

7.3 Quantitative systems biology (2024 DIP-MS)

The 2024 Nature Methods study reports prefoldin complex mapping with n = 3 biologically independent replicates and quantitative coelution and structural similarity metrics (TM score > 45; TM scores reported as mean ± s.e.m.). These results quantify the robustness of inferred assemblies and support PFDN1-containing canonical and alternative prefoldin complexes. (fabian2024dipmsultradeepinteraction pages 7-8)

Synthesis: Primary functional annotation of human PFDN1 (O60925)

Primary molecular function: PFDN1 is a β-subunit of the canonical cytosolic prefoldin cochaperone complex that binds non-native polypeptides and facilitates their folding by transferring/shuttling them to the CCT/TRiC chaperonin system, with actin and tubulin being key client classes. (chesnel2020theprefoldincomplex pages 18-19, wang2015pfdn1anindicator pages 9-10, fabian2024dipmsultradeepinteraction pages 8-8)

Cellular location of action: Predominantly cytosolic as part of prefoldin assemblies involved in proteostasis and cytoskeletal biogenesis; however, nuclear localization and direct transcriptional promoter interaction have been reported in cancer/EMT settings, supporting context-dependent nuclear roles. (wang2017prefoldin1promotes pages 1-2)

Pathways and processes: PFDN1’s canonical pathway is the prefoldin→CCT/TRiC folding relay for cytoskeletal proteins. In cancer contexts, PFDN1 is implicated mechanistically in EMT/metastasis through (i) TGF-β1-associated EMT via transcriptional repression of cyclin A and (ii) Wnt/β-catenin signaling-associated EMT in gastric cancer, in addition to cytoskeletal reorganization effects that influence motility and growth. (wang2017prefoldin1promotes pages 1-2, zhou2020pfnd1predictspoor pages 1-2, wang2015pfdn1anindicator pages 9-10)

Limitations and evidence gaps (within retrieved corpus)

• 2023–2024 literature in the retrieved set is strongest for prefoldin complex organization (Nature Methods 2024) and prefoldin-like complex dependency in medulloblastoma (Molecular Cell 2024), but less rich for new 2023–2024 PFDN1-specific single-gene mechanistic discoveries.

• Some clinically oriented metrics (e.g., multivariable hazard ratios, AUCs for biomarker performance) are not present in the retrieved excerpts for gastric or lung cancer studies and would require additional full-text extraction beyond the subset retrieved here.

Key source URLs (with publication month/year)

• Frommelt et al., Nature Methods. March 2024. “DIP-MS: ultra-deep interaction proteomics for the deconvolution of protein complexes.” https://doi.org/10.1038/s41592-024-02211-y (fabian2024dipmsultradeepinteraction pages 7-8)

• Hofman et al., Molecular Cell. January 2024. “Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.” https://doi.org/10.1016/j.molcel.2023.12.003 (hofman2024translationofnoncanonical pages 57-57)

• Wang et al., Medical Oncology. November 2015. “PFDN1, an indicator for colorectal cancer prognosis, enhances tumor cell proliferation and motility through cytoskeletal reorganization.” https://doi.org/10.1007/s12032-015-0710-z (wang2015pfdn1anindicator pages 9-10)

• Wang et al., Oncogene. October 2017. “Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin A expression.” https://doi.org/10.1038/onc.2016.257 (wang2017prefoldin1promotes pages 1-2)

• Tahmaz et al., Frontiers in Cell and Developmental Biology. January 2022. “Prefoldin Function in Cellular Protein Homeostasis and Human Diseases.” https://doi.org/10.3389/fcell.2021.816214 (tahmaz2022prefoldinfunctionin pages 8-9)

• Herranz-Montoya et al., iScience. November 2021. “A comprehensive analysis of prefoldins and their implication in cancer.” https://doi.org/10.1016/j.isci.2021.103273 (herranzmontoya2021acomprehensiveanalysis pages 18-20)

References

(chesnel2020theprefoldincomplex pages 18-19): Franck Chesnel, Anne Couturier, Adrien Alusse, Jean-Philippe Gagné, Guy G. Poirier, Dominique Jean, François-Michel Boisvert, Pauline Hascoet, Luc Paillard, Yannick Arlot-Bonnemains, and Xavier Le Goff. The prefoldin complex stabilizes the von hippel-lindau protein against aggregation and degradation. PLOS Genetics, 16:e1009183, Nov 2020. URL: https://doi.org/10.1371/journal.pgen.1009183, doi:10.1371/journal.pgen.1009183. This article has 16 citations and is from a domain leading peer-reviewed journal.
(chesnel2020theprefoldincomplex pages 1-2): Franck Chesnel, Anne Couturier, Adrien Alusse, Jean-Philippe Gagné, Guy G. Poirier, Dominique Jean, François-Michel Boisvert, Pauline Hascoet, Luc Paillard, Yannick Arlot-Bonnemains, and Xavier Le Goff. The prefoldin complex stabilizes the von hippel-lindau protein against aggregation and degradation. PLOS Genetics, 16:e1009183, Nov 2020. URL: https://doi.org/10.1371/journal.pgen.1009183, doi:10.1371/journal.pgen.1009183. This article has 16 citations and is from a domain leading peer-reviewed journal.
(fabian2024dipmsultradeepinteraction pages 7-8): Fabian Frommelt, Andrea Fossati, Federico Uliana, Fabian Wendt, Peng Xue, Moritz Heusel, Bernd Wollscheid, Ruedi Aebersold, Rodolfo Ciuffa, and Matthias Gstaiger. Dip-ms: ultra-deep interaction proteomics for the deconvolution of protein complexes. Nature Methods, 21:635-647, Mar 2024. URL: https://doi.org/10.1038/s41592-024-02211-y, doi:10.1038/s41592-024-02211-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(wang2015pfdn1anindicator pages 9-10): Puxiongzhi Wang, Jingkun Zhao, Xiao Yang, Shaopei Guan, Hao Feng, Dingpei Han, Jun Lu, Baochi Ou, Runsen Jin, Jing Sun, Yaping Zong, Bo Feng, Junjun Ma, Aiguo Lu, and Minhua Zheng. Pfdn1, an indicator for colorectal cancer prognosis, enhances tumor cell proliferation and motility through cytoskeletal reorganization. Medical Oncology, 32:1-13, Nov 2015. URL: https://doi.org/10.1007/s12032-015-0710-z, doi:10.1007/s12032-015-0710-z. This article has 49 citations and is from a peer-reviewed journal.
(chesnel2020theprefoldincomplex pages 5-6): Franck Chesnel, Anne Couturier, Adrien Alusse, Jean-Philippe Gagné, Guy G. Poirier, Dominique Jean, François-Michel Boisvert, Pauline Hascoet, Luc Paillard, Yannick Arlot-Bonnemains, and Xavier Le Goff. The prefoldin complex stabilizes the von hippel-lindau protein against aggregation and degradation. PLOS Genetics, 16:e1009183, Nov 2020. URL: https://doi.org/10.1371/journal.pgen.1009183, doi:10.1371/journal.pgen.1009183. This article has 16 citations and is from a domain leading peer-reviewed journal.
(fabian2024dipmsultradeepinteraction pages 8-8): Fabian Frommelt, Andrea Fossati, Federico Uliana, Fabian Wendt, Peng Xue, Moritz Heusel, Bernd Wollscheid, Ruedi Aebersold, Rodolfo Ciuffa, and Matthias Gstaiger. Dip-ms: ultra-deep interaction proteomics for the deconvolution of protein complexes. Nature Methods, 21:635-647, Mar 2024. URL: https://doi.org/10.1038/s41592-024-02211-y, doi:10.1038/s41592-024-02211-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(wang2017prefoldin1promotes pages 1-2): D. Wang, W. Shi, Y. Tang, Y. Liu, K. He, Y. Hu, J. Li, Y. Yang, and J. Song. Prefoldin 1 promotes emt and lung cancer progression by suppressing cyclin a expression. Oncogene, 36:885-898, Oct 2017. URL: https://doi.org/10.1038/onc.2016.257, doi:10.1038/onc.2016.257. This article has 74 citations and is from a domain leading peer-reviewed journal.
(zhou2020pfnd1predictspoor pages 1-2): Cheng Zhou, Zhiyuan Guo, Liqun Xu, Haohai Jiang, Pengfei Sun, Xinguo Zhu, and Xiangming Mu. Pfnd1 predicts poor prognosis of gastric cancer and promotes cell metastasis by activating the wnt/β-catenin pathway. OncoTargets and therapy, 13:3177-3186, Apr 2020. URL: https://doi.org/10.2147/ott.s236929, doi:10.2147/ott.s236929. This article has 19 citations.
(fabian2024dipmsultradeepinteraction media 5b2ee584): Fabian Frommelt, Andrea Fossati, Federico Uliana, Fabian Wendt, Peng Xue, Moritz Heusel, Bernd Wollscheid, Ruedi Aebersold, Rodolfo Ciuffa, and Matthias Gstaiger. Dip-ms: ultra-deep interaction proteomics for the deconvolution of protein complexes. Nature Methods, 21:635-647, Mar 2024. URL: https://doi.org/10.1038/s41592-024-02211-y, doi:10.1038/s41592-024-02211-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(fabian2024dipmsultradeepinteraction media 01045fb5): Fabian Frommelt, Andrea Fossati, Federico Uliana, Fabian Wendt, Peng Xue, Moritz Heusel, Bernd Wollscheid, Ruedi Aebersold, Rodolfo Ciuffa, and Matthias Gstaiger. Dip-ms: ultra-deep interaction proteomics for the deconvolution of protein complexes. Nature Methods, 21:635-647, Mar 2024. URL: https://doi.org/10.1038/s41592-024-02211-y, doi:10.1038/s41592-024-02211-y. This article has 26 citations and is from a highest quality peer-reviewed journal.
(hofman2024translationofnoncanonical pages 57-57): Damon A. Hofman, Jorge Ruiz-Orera, Ian Yannuzzi, Rakesh Murugesan, Adam Brown, Karl R. Clauser, Alexandra L. Condurat, Jip T. van Dinter, Sem A.G. Engels, Amy Goodale, Jasper van der Lugt, Tanaz Abid, Li Wang, Kevin N. Zhou, Jayne Vogelzang, Keith L. Ligon, Timothy N. Phoenix, Jennifer A. Roth, David E. Root, Norbert Hubner, Todd R. Golub, Pratiti Bandopadhayay, Sebastiaan van Heesch, and John R. Prensner. Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma. Molecular Cell, 84:261-276.e18, Jan 2024. URL: https://doi.org/10.1016/j.molcel.2023.12.003, doi:10.1016/j.molcel.2023.12.003. This article has 67 citations and is from a highest quality peer-reviewed journal.
(herranzmontoya2021acomprehensiveanalysis pages 18-20): Irene Herranz-Montoya, Solip Park, and Nabil Djouder. A comprehensive analysis of prefoldins and their implication in cancer. iScience, 24:103273, Nov 2021. URL: https://doi.org/10.1016/j.isci.2021.103273, doi:10.1016/j.isci.2021.103273. This article has 25 citations and is from a peer-reviewed journal.
(tahmaz2022prefoldinfunctionin pages 8-9): Ismail Tahmaz, Somayeh Shahmoradi Ghahe, and Ulrike Topf. Prefoldin function in cellular protein homeostasis and human diseases. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.816214, doi:10.3389/fcell.2021.816214. This article has 50 citations.

Citations

fabian2024dipmsultradeepinteraction pages 7-8
hofman2024translationofnoncanonical pages 57-57
herranzmontoya2021acomprehensiveanalysis pages 18-20
tahmaz2022prefoldinfunctionin pages 8-9
chesnel2020theprefoldincomplex pages 18-19
chesnel2020theprefoldincomplex pages 1-2
chesnel2020theprefoldincomplex pages 5-6
fabian2024dipmsultradeepinteraction pages 8-8
https://doi.org/10.1038/s41592-024-02211-y
https://doi.org/10.1016/j.molcel.2023.12.003
https://doi.org/10.1007/s12032-015-0710-z
https://doi.org/10.1038/onc.2016.257
https://doi.org/10.3389/fcell.2021.816214
https://doi.org/10.1016/j.isci.2021.103273
https://doi.org/10.1371/journal.pgen.1009183,
https://doi.org/10.1038/s41592-024-02211-y,
https://doi.org/10.1007/s12032-015-0710-z,
https://doi.org/10.1038/onc.2016.257,
https://doi.org/10.2147/ott.s236929,
https://doi.org/10.1016/j.molcel.2023.12.003,
https://doi.org/10.1016/j.isci.2021.103273,
https://doi.org/10.3389/fcell.2021.816214,

📄 View Raw YAML

id: O60925
gene_symbol: PFDN1
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PFDN1 (Prefoldin subunit 1) encodes a beta-type subunit of the heterohexameric
  prefoldin complex (also known as GimC). The prefoldin complex is a jellyfish-shaped
  molecular chaperone composed of two alpha subunits (PFDN3, PFDN5) and four beta
  subunits (PFDN1, PFDN2, PFDN4, PFDN6). Prefoldin functions as a co-chaperone/holdase
  that captures unfolded nascent polypeptides -- primarily actin and tubulin -- and
  delivers them to the group II chaperonin TRiC/CCT for ATP-dependent folding. The
  prefoldin-TRiC interaction is mediated through a conserved electrostatic interface,
  and PFD alternates between open "latched" and closed "engaged" conformations during
  substrate transfer (PMID:30955883). The client repertoire extends beyond cytoskeletal
  proteins: prefoldin stabilizes the von Hippel-Lindau tumor suppressor protein (pVHL)
  against aggregation and degradation, with prefoldin knockdown reducing pVHL expression
  (DOI:10.1371/journal.pgen.1009183). A 2024 DIP-MS (deep interactome profiling) study
  resolved canonical and alternative prefoldin assemblies in human cells, demonstrating
  that prefoldin may exist in modular complex isoforms potentially underlying
  context-specific functions (DOI:10.1038/s41592-024-02211-y). Beyond its cytosolic
  chaperone role, PFDN1 has non-canonical nuclear functions in cancer contexts: it can
  repress cyclin A transcription via direct promoter interaction, promoting EMT and
  metastasis through a TGF-beta1/PFDN1/cyclin A axis in lung cancer
  (DOI:10.1038/onc.2016.257). Prefoldin has also been shown to inhibit amyloid-beta
  fibrillation and alpha-synuclein aggregation, suggesting roles in neuroprotection.
  PFDN1 is ubiquitously expressed and located on chromosome 5.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0006457 "protein folding" is a well-supported core function of PFDN1.
      This IBA annotation was inferred from phylogenetic analysis (PANTHER) with
      evidence from yeast GimC/prefoldin (SGD:S000003715), Arabidopsis, and human
      PFDN1 itself. The prefoldin complex is a bona fide co-chaperone that captures
      unfolded nascent polypeptides (primarily actin and tubulin) and delivers them
      to TRiC/CCT for ATP-dependent folding (PMID:9630229). Gestaut et al. 2019
      (PMID:30955883) showed that PFD enhances the rate and yield of TRiC-mediated
      folding, directly demonstrating involvement in protein folding. The Reactome
      pathway R-HSA-389957 "Prefoldin mediated transfer of substrate to CCT/TriC"
      also supports this annotation. This is the central biological process for
      PFDN1.
    action: ACCEPT
    reason: >-
      Protein folding is the core biological process for all prefoldin subunits.
      The IBA annotation is phylogenetically well-supported and consistent with
      the extensive experimental literature demonstrating prefoldin's role in
      delivering substrates to TRiC/CCT for folding (PMID:9630229, PMID:30955883).
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        We describe the discovery of a heterohexameric chaperone protein, prefoldin,
        based on its ability to capture unfolded actin. Prefoldin binds specifically
        to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962).
      This IBA annotation was inferred from phylogenetic analysis (PANTHER) with
      evidence from yeast (SGD:S000003715) and human PFDN1 itself. While prefoldin
      does indeed bind unfolded proteins, the term "unfolded protein binding" is a
      pure binding term that fails to capture the functional significance of this
      interaction. Prefoldin acts as a holdase/transfer chaperone: it captures
      unfolded substrates (primarily actin and tubulin) and delivers them to the
      TRiC/CCT chaperonin for folding. As described in Vainberg et al. 1998
      (PMID:9630229), "Prefoldin binds specifically to cytosolic chaperonin (c-cpn)
      and transfers target proteins to it." The more appropriate term is GO:0044183
      "protein folding chaperone" which captures the functional chaperone activity
      rather than just substrate binding. Notably, PFDN1 already has an IBA annotation
      to GO:0044183 in this same annotation set.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. The term describes only a binding activity
      and does not capture the chaperone function of prefoldin. Prefoldin is a
      molecular chaperone that binds unfolded substrates and delivers them to
      TRiC/CCT for folding (PMID:9630229, PMID:30955883). GO:0044183 "protein
      folding chaperone" (defined as "Binding to a protein or a protein-containing
      complex to assist the protein folding process") is the recommended replacement
      and already exists as a separate IBA annotation for this gene.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:9630229
    - PMID:30955883
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it.
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD alternates between an open "latched" conformation and a closed "engaged"
        conformation that aligns the PFD-TRiC substrate binding chambers.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0005737 "cytoplasm" is an appropriate cellular component annotation for
      PFDN1. This IBA annotation was inferred from phylogenetic analysis (PANTHER)
      with evidence from C. elegans (WB:WBGene00007443). The prefoldin complex
      is a cytoplasmic chaperone that operates in the cytosol to capture unfolded
      nascent polypeptides and deliver them to the cytosolic chaperonin TRiC/CCT
      (PMID:9630229). The UniProt GO cross-references list this annotation, and
      the GOA qualifier "is_active_in" confirms that PFDN1 is active in the
      cytoplasm. Liang et al. 2020 (PMID:32699605) describe prefoldin as "a
      cytoplasmic chaperone protein." The term "cytoplasm" is appropriately broad,
      as a more specific CC annotation to "prefoldin complex" (GO:0016272) is
      already present in this annotation set. Having both is correct: one describes
      the subcellular location and the other describes the complex membership.
    action: ACCEPT
    reason: >-
      PFDN1 operates as part of the cytoplasmic prefoldin complex. The cytoplasm
      annotation is well-supported and appropriately broad, complementing the more
      specific prefoldin complex (GO:0016272) annotation. The IBA phylogenetic
      inference is sound (PMID:9630229, PMID:32699605).
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it.
    - reference_id: PMID:32699605
      supporting_text: >-
        As a cytoplasmic chaperone protein, the prefoldin complex is a hybrid
        oligomer assembled from six different proteins (six subunits).
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      GO:0044183 "protein folding chaperone" (defined as "Binding to a protein or
      a protein-containing complex to assist the protein folding process") is the
      most appropriate molecular function term for PFDN1. This IBA annotation was
      inferred from phylogenetic analysis (PANTHER) with evidence from human PFDN1
      itself. Prefoldin functions as a holdase/transfer chaperone that captures
      unfolded nascent polypeptides and delivers them to TRiC/CCT for folding
      (PMID:9630229). Gestaut et al. 2019 (PMID:30955883) demonstrated that the
      PFD-TRiC supra-chaperone assembly enhances folding rates and suppresses
      non-productive reaction cycles. This term precisely captures the functional
      role of PFDN1 as a co-chaperone that assists in protein folding, and is also
      the recommended replacement for the obsoleting GO:0051082 "unfolded protein
      binding."
    action: ACCEPT
    reason: >-
      This is the core molecular function of PFDN1. The prefoldin complex is a
      bona fide protein folding chaperone that captures unfolded substrates and
      delivers them to TRiC/CCT (PMID:9630229, PMID:30955883). The IBA annotation
      is phylogenetically well-supported and represents the best available MF term
      for prefoldin subunits.
    supported_by:
    - reference_id: PMID:9630229
      supporting_text: >-
        We describe the discovery of a heterohexameric chaperone protein, prefoldin,
        based on its ability to capture unfolded actin. Prefoldin binds specifically
        to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0006457 "protein folding" inferred electronically from InterPro domain
      mapping (IPR002777, the prefoldin beta-like domain). This IEA annotation is
      consistent with the IBA and IDA annotations to the same term, and with the
      well-established role of the prefoldin complex in protein folding (PMID:9630229).
      The InterPro-to-GO mapping is appropriate for this domain.
    action: ACCEPT
    reason: >-
      The IEA annotation to protein folding via InterPro is correct and consistent
      with the higher-confidence IBA and IDA annotations. The prefoldin beta-like
      domain (IPR002777) is specifically associated with the protein folding function
      of the prefoldin complex (PMID:9630229, PMID:30955883).
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0016272 "prefoldin complex" inferred electronically from InterPro domain
      mapping (IPR002777, the prefoldin beta-like domain). PFDN1 is one of the four
      beta subunits (PFDN1, PFDN2, PFDN4, PFDN6) of the heterohexameric prefoldin
      complex (PMID:9630229, PMID:32699605). The complex is also registered in
      ComplexPortal as CPX-6149 and CPX-25767. This IEA annotation is consistent
      with the IDA annotations to the same term from PMID:30955883 and PMID:23614719.
    action: ACCEPT
    reason: >-
      PFDN1 is a core structural subunit of the prefoldin complex. The IEA mapping
      from the prefoldin beta-like domain (IPR002777) to prefoldin complex membership
      is appropriate and consistent with experimental evidence (PMID:9630229,
      PMID:30955883).
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      GO:0032991 "protein-containing complex" was inferred electronically by the
      ARBA machine learning model (ARBA:ARBA00028902). While technically correct --
      PFDN1 is part of the prefoldin complex, which is indeed a protein-containing
      complex -- this annotation is redundant and overly general given the more
      specific GO:0016272 "prefoldin complex" annotation that is already present
      in this annotation set from both IEA (InterPro) and IDA (PMID:30955883,
      PMID:23614719) evidence. The term "protein-containing complex" adds no
      informational value beyond what is already captured.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      This is an overly general annotation. PFDN1 is part of the prefoldin complex
      (GO:0016272), which is a child term of protein-containing complex. The more
      specific term is already annotated with both IEA and IDA evidence. The generic
      "protein-containing complex" adds no useful information.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962).
      This IEA annotation was inferred electronically from InterPro domain mapping
      (IPR002777, the prefoldin beta-like domain). The InterPro-to-GO mapping
      associates the prefoldin domain with unfolded protein binding, which is
      functionally accurate in that prefoldin subunits do contact unfolded substrates.
      However, since the term is being obsoleted, the annotation should be replaced
      with GO:0044183 "protein folding chaperone" which better describes the
      functional role of the prefoldin complex as a holdase/transfer chaperone that
      delivers substrates to TRiC/CCT. As noted by Liang et al. 2020 (PMID:32699605),
      "The prefoldin complex helps protein fold correctly and prevents aggregation by
      providing class II chaperones ... with a linear, unnatural substrate in the
      cytoplasm."
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. While the InterPro mapping correctly identifies
      that the prefoldin domain binds unfolded proteins, the replacement term
      GO:0044183 "protein folding chaperone" better captures the functional role
      of prefoldin as a chaperone that assists in protein folding by delivering
      unfolded substrates to the TRiC/CCT chaperonin (PMID:32699605, PMID:9630229).
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:32699605
    - PMID:9630229
    supported_by:
    - reference_id: PMID:32699605
      supporting_text: >-
        The prefoldin complex helps protein fold correctly and prevents aggregation
        by providing class II chaperones (Hsp60 molecular chaperones found in
        archaebacteria and eukaryotic cytoplasm) with a linear, unnatural substrate
        in the cytoplasm [2]
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16169070
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9Y2X7/GIT1) from Stelzl
      et al. 2005 (PMID:16169070), a large-scale yeast two-hybrid screen of the
      human proteome. The interaction between PFDN1 and GIT1 (G protein-coupled
      receptor kinase interacting ArfGAP 1) was identified in this high-throughput
      screen. GIT1 is involved in cell signaling and cytoskeletal organization.
      While this could represent a biologically relevant interaction (GIT1 is
      involved in cytoskeletal remodeling, and prefoldin assists in actin/tubulin
      folding), the "protein binding" term is uninformative. However, the
      interaction itself is from a large-scale screen and may not reflect a
      direct functional relationship.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is an uninformative term that does not describe any
      specific molecular function. The interaction with GIT1 (Q9Y2X7) was detected
      in a high-throughput Y2H screen (PMID:16169070), and while the interaction
      may be real, the GO term provides no functional insight. More informative
      annotations such as GO:0044183 "protein folding chaperone" already capture
      the core binding function of PFDN1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16876117
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2) from Tsao
      et al. 2006 (PMID:16876117). This study used yeast two-hybrid and
      co-immunoprecipitation to demonstrate that HCV F protein interacts with
      PFDN2, and that HCV F protein "impeded the interaction between prefoldin 1
      and 2." This confirms the PFDN1-PFDN2 interaction, which is expected since
      they are both subunits of the same heterohexameric prefoldin complex. The
      UniProt record confirms this interaction (NbExp=6). However, "protein binding"
      is uninformative -- this interaction reflects prefoldin complex assembly
      rather than a generic binding function. The annotation is not wrong but
      the term is too vague to be useful.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The PFDN1-PFDN2 interaction reflects
      subunit assembly within the prefoldin complex and is already captured by
      the GO:0016272 "prefoldin complex" CC annotation. The PMID:16876117 study
      was primarily about HCV F protein interaction with PFDN2, not PFDN1 function.
    supported_by:
    - reference_id: PMID:16876117
      supporting_text: >-
        In the yeast three-hybrid system, it was found that expression of HCV F
        protein impeded the interaction between prefoldin 1 and 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21900206
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9Y2X7/GIT1) from Vinayagam
      et al. 2011 (PMID:21900206), a directed protein interaction network study.
      This is a second independent detection of the PFDN1-GIT1 interaction (also
      seen in PMID:16169070). While the replication adds some confidence that the
      interaction is real, "protein binding" remains uninformative as a GO
      annotation for PFDN1. The biological significance of a PFDN1-GIT1 interaction
      is unclear.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. This high-throughput interaction screen
      detection of PFDN1-GIT1 binding does not provide functional insight. The
      core molecular function of PFDN1 is already captured by GO:0044183
      "protein folding chaperone."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2) from Huttlin
      et al. 2017 (PMID:28514442), the BioPlex human interactome study. This is
      another independent detection of the PFDN1-PFDN2 intra-complex interaction,
      which is expected for subunits of the same hexameric complex. The "protein
      binding" term is uninformative and the interaction is already captured by
      the prefoldin complex membership annotation (GO:0016272).
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The PFDN1-PFDN2 interaction reflects
      co-membership in the prefoldin complex, already captured by GO:0016272.
      This high-throughput interactome study provides no additional functional
      insight beyond complex membership.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9NPF5/DMAP1) from Luck
      et al. 2020 (PMID:32296183), a reference map of the human binary protein
      interactome (HuRI). DMAP1 (DNA methyltransferase 1-associated protein 1) is
      a component of NuA4/TIP60 histone acetyltransferase complex. The UniProt
      record for PFDN1 lists this interaction (NbExp=3). While the interaction may
      be real, its biological significance for PFDN1 function is unclear. DMAP1 is
      a nuclear protein whereas PFDN1 functions primarily in the cytoplasm. The
      "protein binding" term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. The PFDN1-DMAP1 interaction was detected
      in a high-throughput binary interactome screen. The biological relevance is
      unclear given that PFDN1 is cytoplasmic and DMAP1 is nuclear. The core
      molecular function of PFDN1 is already captured by GO:0044183.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2 and
      UniProtKB:Q9Y2X7/GIT1) from Huttlin et al. 2021 (PMID:33961781), a dual
      proteome-scale network study of the human interactome. This confirms
      previously observed interactions: the PFDN1-PFDN2 interaction (intra-complex)
      and the PFDN1-GIT1 interaction. Both interactions have been detected in
      multiple independent studies. However, "protein binding" remains uninformative
      as a functional annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. These are replications of previously
      observed interactions (PFDN1-PFDN2 intra-complex; PFDN1-GIT1) that do not
      add functional insight beyond what is captured by GO:0016272 (prefoldin
      complex) and GO:0044183 (protein folding chaperone).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      GO:0005515 "protein binding" (IPI with UniProtKB:Q9UHV9/PFDN2 and
      UniProtKB:Q9Y2X7/GIT1) from multimodal cell maps study (PMID:40205054).
      This is yet another replication of the PFDN1-PFDN2 and PFDN1-GIT1
      interactions. The PFDN1-PFDN2 interaction is expected as both are subunits
      of the prefoldin complex. The "protein binding" term remains uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is uninformative. This is a further replication of known
      interactions (PFDN1-PFDN2, PFDN1-GIT1) from a large-scale study. The
      relevant functions are already captured by more specific annotations
      (GO:0044183, GO:0016272).
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:32699605
  review:
    summary: >-
      GO:0006457 "protein folding" (NAS) from ComplexPortal, citing Liang et al.
      2020 (PMID:32699605), a comprehensive review of prefoldin complex functions.
      The review describes how "the prefoldin complex helps protein fold correctly
      and prevents aggregation by providing class II chaperones ... with a linear,
      unnatural substrate in the cytoplasm." This NAS annotation is consistent with
      the IBA and IDA annotations to the same term and is well-supported by the
      review literature.
    action: ACCEPT
    reason: >-
      Protein folding is the core biological process for PFDN1. This NAS annotation
      from ComplexPortal cites a well-sourced review (PMID:32699605) that accurately
      describes the protein folding function of the prefoldin complex. Consistent
      with IBA and IDA evidence to the same term.
    supported_by:
    - reference_id: PMID:32699605
      supporting_text: >-
        The prefoldin complex helps protein fold correctly and prevents aggregation
        by providing class II chaperones (Hsp60 molecular chaperones found in
        archaebacteria and eukaryotic cytoplasm) with a linear, unnatural substrate
        in the cytoplasm [2]
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:34761191
  review:
    summary: >-
      GO:0006457 "protein folding" (NAS) from ComplexPortal, citing Herranz-Montoya
      et al. 2021 (PMID:34761191), a comprehensive analysis of prefoldins and their
      implication in cancer. The review describes prefoldins as "evolutionary conserved
      co-chaperones" that "act as co-chaperones escorting misfolded or non-native
      proteins to group II chaperonins." This NAS annotation is consistent with the
      IBA and IDA annotations to the same term and is well-supported.
    action: ACCEPT
    reason: >-
      Protein folding is the core biological process for PFDN1. This NAS annotation
      from ComplexPortal cites a comprehensive review (PMID:34761191) that accurately
      describes the co-chaperone function of prefoldin subunits. Consistent with
      IBA and IDA evidence.
    supported_by:
    - reference_id: PMID:34761191
      supporting_text: >-
        PFDNs are prevalently organized into hetero-hexameric complexes. Although
        they have been overlooked since their discovery and their functions remain
        elusive, several reports indicate they act as co-chaperones escorting
        misfolded or non-native proteins to group II chaperonins.
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: NAS
  original_reference_id: PMID:34761191
  review:
    summary: >-
      GO:0050821 "protein stabilization" (NAS) from ComplexPortal, citing
      Herranz-Montoya et al. 2021 (PMID:34761191). The GO definition of protein
      stabilization is "Any process involved in maintaining the structure and
      integrity of a protein and preventing it from degradation or aggregation."
      Prefoldin does prevent aggregation of unfolded substrates by capturing them
      and delivering them to TRiC/CCT (PMID:9630229). However, "protein
      stabilization" typically implies maintaining a folded protein in its native
      state, whereas prefoldin acts on unfolded nascent polypeptides as a holdase
      and transfer chaperone. The term is not entirely wrong -- prefoldin does
      prevent aggregation -- but it mischaracterizes the nature of the chaperone
      activity. The more accurate process annotation is GO:0006457 "protein
      folding," which is already well-annotated.
    action: KEEP_AS_NON_CORE
    reason: >-
      While prefoldin does prevent protein aggregation (which is part of the GO
      definition of protein stabilization), the primary function is not to
      stabilize already-folded proteins but rather to capture unfolded substrates
      and transfer them to TRiC/CCT for folding. The annotation is not wrong
      but represents a secondary aspect of prefoldin function rather than its
      core activity. The core process (protein folding, GO:0006457) is already
      well-annotated with IBA, IDA, and NAS evidence.
    supported_by:
    - reference_id: PMID:34761191
      supporting_text: >-
        PFDNs are prevalently organized into hetero-hexameric complexes. Although
        they have been overlooked since their discovery and their functions remain
        elusive, several reports indicate they act as co-chaperones escorting
        misfolded or non-native proteins to group II chaperonins.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0006457 "protein folding" (IDA) from Gestaut et al. 2019 (PMID:30955883),
      which used cryo-EM, crosslinking mass spectrometry, and biochemical
      reconstitution to characterize the structural and functional interplay between
      the prefoldin (PFD) complex and TRiC/CCT chaperonin. The study demonstrates
      that "PFD can act after TRiC bound its substrates to enhance the rate and yield
      of the folding reaction, suppressing non-productive reaction cycles," directly
      showing involvement in protein folding. This is the highest-quality direct
      experimental evidence for the protein folding function of the prefoldin complex.
    action: ACCEPT
    reason: >-
      This IDA annotation is supported by strong direct experimental evidence from
      Gestaut et al. 2019 (PMID:30955883), which demonstrated through cryo-EM and
      biochemical approaches that the PFD-TRiC supra-chaperone assembly enhances
      protein folding rates. Protein folding is the core biological process for
      PFDN1.
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
    - reference_id: PMID:30955883
      supporting_text: >-
        The supra-chaperone assembly formed by PFD and TRiC is essential to
        prevent toxic conformations and ensure effective cellular proteostasis.
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0016272 "prefoldin complex" (IDA) from Gestaut et al. 2019 (PMID:30955883).
      This study used reconstituted human prefoldin complex (containing all six
      subunits including PFDN1) and characterized its structure and function through
      cryo-EM, crosslinking mass spectrometry, and biochemical assays. The study
      resolved the architecture of the PFD-TRiC supra-chaperone complex, directly
      demonstrating that PFDN1 is a component of the prefoldin complex. The cryo-EM
      structures (PDB: 6NR8, 6NR9, 6NRB, 6NRC, 6NRD) include PFDN1 as a structural
      component.
    action: ACCEPT
    reason: >-
      PFDN1 is a core structural subunit of the prefoldin complex. This IDA
      annotation is supported by high-resolution cryo-EM structural data from
      Gestaut et al. 2019 (PMID:30955883) that directly demonstrates PFDN1 as a
      component of the human prefoldin complex.
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        Maintaining proteostasis in eukaryotic protein folding involves cooperation
        of distinct chaperone systems. To understand how the essential ring-shaped
        chaperonin TRiC/CCT cooperates with the chaperone prefoldin/GIMc (PFD), we
        integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry
        and biochemical and cellular approaches to elucidate the structural and
        functional interplay between TRiC/CCT and PFD.
- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      GO:0051082 "unfolded protein binding" is being obsoleted (go-ontology#30962).
      This IDA annotation cites Gestaut et al. 2019 (PMID:30955883), which used
      cryo-EM, crosslinking mass spectrometry, and biochemical reconstitution to
      characterize the structural and functional interplay between the prefoldin
      (PFD) complex and TRiC/CCT chaperonin. The study demonstrates that prefoldin
      associates with TRiC through a conserved electrostatic interface and undergoes
      conformational cycling between "latched" (open) and "engaged" (closed) states
      during substrate transfer. Critically, the paper shows that PFD functions not
      merely as a passive binder of unfolded substrates but as an active co-chaperone
      that "can act after TRiC bound its substrates to enhance the rate and yield of
      the folding reaction, suppressing non-productive reaction cycles." This
      demonstrates prefoldin is a bona fide protein folding chaperone. GO:0044183
      "protein folding chaperone" is the appropriate replacement, capturing the
      functional role of prefoldin in the chaperone-assisted folding pathway.
    action: MODIFY
    reason: >-
      GO:0051082 is being obsoleted. Gestaut et al. 2019 (PMID:30955883)
      demonstrates that prefoldin functions as a co-chaperone/holdase that
      cooperates with TRiC/CCT in substrate folding, not merely as an unfolded
      protein binder. The study shows prefoldin enhances the rate and yield of
      TRiC-mediated folding and that disrupting the PFD-TRiC interaction leads
      to accumulation of amyloid aggregates in vivo. GO:0044183 "protein folding
      chaperone" accurately describes this co-chaperone activity. Note that while
      prefoldin itself functions primarily as a holdase (it does not fold proteins
      on its own but transfers them to TRiC), the GO:0044183 definition ("Binding
      to a protein or a protein-containing complex to assist the protein folding
      process") appropriately encompasses this transfer/holdase function.
    proposed_replacement_terms:
    - id: GO:0044183
      label: protein folding chaperone
    additional_reference_ids:
    - PMID:9630229
    supported_by:
    - reference_id: PMID:30955883
      supporting_text: >-
        PFD can act after TRiC bound its substrates to enhance the rate and yield
        of the folding reaction, suppressing non-productive reaction cycles.
    - reference_id: PMID:30955883
      supporting_text: >-
        Disrupting the TRiC-PFD interaction in vivo is strongly deleterious,
        leading to accumulation of amyloid aggregates.
    - reference_id: PMID:30955883
      supporting_text: >-
        The supra-chaperone assembly formed by PFD and TRiC is essential to
        prevent toxic conformations and ensure effective cellular proteostasis.
    - reference_id: PMID:9630229
      supporting_text: >-
        Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers
        target proteins to it. ... prefoldin promotes folding in an environment in
        which there are many competing pathways for nonnative proteins.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      GO:0001540 "amyloid-beta binding" (IDA) from Sorgjerd et al. 2013
      (PMID:23614719). This study demonstrated that recombinant human prefoldin
      (hPFD) inhibits amyloid-beta (Abeta 1-42) fibrillation in vitro and induces
      formation of soluble Abeta oligomers with reduced toxicity. The study used
      thioflavin T measurements and immunoblotting to show that hPFD directly
      interacts with Abeta peptides and modifies their aggregation pathway. While
      this demonstrates that the prefoldin complex can bind Abeta, this is not the
      core function of PFDN1 -- it reflects the general chaperone/holdase property
      of prefoldin applied to an amyloidogenic substrate. The annotation was made
      on the intact prefoldin complex, not PFDN1 individually.
    action: KEEP_AS_NON_CORE
    reason: >-
      Amyloid-beta binding is a secondary, non-core function that reflects the
      general holdase/chaperone activity of the prefoldin complex applied to an
      amyloidogenic substrate. The study (PMID:23614719) used the intact hexameric
      complex rather than individual PFDN1. While the data are solid, this
      represents a peripheral function compared to the core role in actin/tubulin
      folding via TRiC/CCT delivery.
    supported_by:
    - reference_id: PMID:23614719
      supporting_text: >-
        we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42)
        aggregation in vitro and found that hPFD inhibited Abeta fibrillation and
        induced formation of soluble Abeta oligomers.
- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      GO:0016272 "prefoldin complex" (IDA) from Sorgjerd et al. 2013
      (PMID:23614719). This study expressed and purified recombinant human prefoldin
      complex (hPFD) to investigate its effect on amyloid-beta aggregation. The
      successful reconstitution and purification of the hexameric complex containing
      PFDN1 provides direct evidence for PFDN1 membership in the prefoldin complex.
      This is consistent with the IDA annotation from PMID:30955883 and the IEA
      annotation from InterPro.
    action: ACCEPT
    reason: >-
      PFDN1 is a core structural subunit of the prefoldin complex. This IDA
      annotation from PMID:23614719 provides independent experimental evidence
      through reconstitution of the human prefoldin hexamer, consistent with
      the structural data from PMID:30955883.
    supported_by:
    - reference_id: PMID:23614719
      supporting_text: >-
        Prefoldin (PFD) is a molecular chaperone that prevents aggregation of
        misfolded proteins.
- term:
    id: GO:1905907
    label: negative regulation of amyloid fibril formation
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      GO:1905907 "negative regulation of amyloid fibril formation" (IDA) from
      Sorgjerd et al. 2013 (PMID:23614719). The study demonstrated that
      recombinant human prefoldin "inhibited Abeta fibrillation and induced
      formation of soluble Abeta oligomers" that were 30-40% less toxic than Abeta
      fibrils. Thioflavin T measurements confirmed reduced fibril formation. While
      the experimental evidence is sound, this represents a non-core function of
      the prefoldin complex -- an extension of its general holdase/chaperone
      properties to amyloidogenic substrates rather than its primary role in
      actin/tubulin folding. The study was performed on the intact hexameric
      complex, not PFDN1 individually.
    action: KEEP_AS_NON_CORE
    reason: >-
      The experimental evidence from PMID:23614719 is solid, but this is a
      secondary function reflecting the general anti-aggregation properties of
      the prefoldin complex rather than its core role in delivering unfolded
      actin/tubulin to TRiC/CCT. The study was performed in vitro on the intact
      hexameric complex, and the relevance to PFDN1 specifically (as opposed to
      the complex as a whole) is indirect.
    supported_by:
    - reference_id: PMID:23614719
      supporting_text: >-
        we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42)
        aggregation in vitro and found that hPFD inhibited Abeta fibrillation and
        induced formation of soluble Abeta oligomers.
    - reference_id: PMID:23614719
      supporting_text: >-
        Our findings show a relation between cytotoxicity of Abeta oligomers and
        structure and suggest a possible protective role of PFD in AD.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IPI
  original_reference_id: PMID:16876117
  review:
    summary: >-
      GO:0044183 "protein folding chaperone" (IPI with UniProtKB:Q9UHV9/PFDN2)
      from Tsao et al. 2006 (PMID:16876117), annotated by AgBase. This study
      demonstrated that HCV F protein interacts with PFDN2 and that this
      interaction "impeded the interaction between prefoldin 1 and 2," resulting
      in "aberrant organization of tubulin cytoskeleton." The study describes
      prefoldin as "a hexameric molecular chaperone complex ... which delivers
      nascent actin and tubulin proteins to the eukaryotic cytosolic chaperonin
      for facilitated folding." The IPI evidence code is appropriate because the
      chaperone function of PFDN1 was demonstrated through its interaction with
      PFDN2 in the context of prefoldin complex assembly and function. The study
      shows that disrupting the PFDN1-PFDN2 interaction (via HCV F protein)
      impairs the chaperone function of the complex, providing indirect evidence
      that PFDN1 enables protein folding chaperone activity through the complex.
    action: ACCEPT
    reason: >-
      GO:0044183 "protein folding chaperone" is the core molecular function of
      PFDN1. This IPI annotation is supported by PMID:16876117, which demonstrates
      that PFDN1-PFDN2 interaction is essential for prefoldin complex assembly and
      chaperone function. Disruption of this interaction by HCV F protein leads to
      aberrant tubulin cytoskeleton, confirming the functional significance.
    supported_by:
    - reference_id: PMID:16876117
      supporting_text: >-
        Prefoldin 2 is a subunit of a hexameric molecular chaperone complex, named
        prefoldin, which delivers nascent actin and tubulin proteins to the
        eukaryotic cytosolic chaperonin for facilitated folding.
    - reference_id: PMID:16876117
      supporting_text: >-
        In the yeast three-hybrid system, it was found that expression of HCV F
        protein impeded the interaction between prefoldin 1 and 2.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:16169070
  title: 'A human protein-protein interaction network: a resource for annotating the
    proteome.'
  findings: []
- id: PMID:16876117
  title: Interaction of hepatitis C virus F protein with prefoldin 2 perturbs tubulin
    cytoskeleton organization.
  findings: []
- id: PMID:21900206
  title: A directed protein interaction network for investigating intracellular signal
    transduction.
  findings: []
- id: PMID:23614719
  title: "Human prefoldin inhibits amyloid-\u03B2 (A\u03B2) fibrillation and contributes\
    \ to formation of nontoxic A\u03B2 aggregates."
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:30955883
  title: The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic
    Interface Essential for Cellular Proteostasis.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32699605
  title: The functions and mechanisms of prefoldin complex and prefoldin-subunits.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34761191
  title: A comprehensive analysis of prefoldins and their implication in cancer.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9630229
  title: 'Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin.'
  findings: []
- id: DOI:10.1371/journal.pgen.1009183
  title: The prefoldin complex stabilizes the von Hippel-Lindau protein against
    aggregation and degradation
  findings:
    - statement: Prefoldin complex physically associates with pVHL in human cells and
        prefoldin knockdown reduces pVHL expression
    - statement: In yeast, prefoldin mutants promote pVHL aggregation, supporting a role
        in client stabilization beyond actin and tubulin
- id: DOI:10.1038/s41592-024-02211-y
  title: DIP-MS ultra-deep interaction proteomics for the deconvolution of protein
    complexes
  findings:
    - statement: DIP-MS resolved canonical and alternative prefoldin assemblies in human
        cells, with PFDN1 as a component, supporting modular complex isoforms
    - statement: Prefoldin subunits show coelution and association patterns linked to
        CCT/TRiC with n equals 3 biologically independent replicates
- id: DOI:10.1038/onc.2016.257
  title: Prefoldin 1 promotes EMT and lung cancer progression by suppressing cyclin
    A expression
  findings:
    - statement: PFDN1 increases during TGF-beta1-induced EMT and localizes to the
        nucleus in cancer contexts
    - statement: PFDN1 represses cyclin A expression by directly interacting with the
        cyclin A promoter near the transcription start site
- id: DOI:10.1007/s12032-015-0710-z
  title: PFDN1 an indicator for colorectal cancer prognosis enhances tumor cell
    proliferation and motility through cytoskeletal reorganization
  findings:
    - statement: PFDN1 knockdown reduces F-actin levels and alpha-tubulin staining
        in colorectal cancer cells, consistent with impaired cytoskeletal homeostasis
    - statement: PFDN1 knockdown in xenografts reduced tumor weight to 346.8 mg versus
        783.4 mg in controls (P less than 0.01)
- id: DOI:10.3389/fcell.2021.816214
  title: Prefoldin function in cellular protein homeostasis and human diseases
  findings:
    - statement: Review emphasizes canonical prefoldin function as transfer of
        cytoskeletal polypeptides to TRiC/CCT while highlighting non-canonical functions
        in transcription regulation and proteasome-dependent degradation
core_functions:
  - description: >-
      PFDN1 is a beta-type subunit of the heterohexameric prefoldin co-chaperone
      complex that captures unfolded nascent polypeptides (primarily actin and tubulin)
      and delivers them to the TRiC/CCT chaperonin for ATP-dependent folding. The
      prefoldin-TRiC supra-chaperone assembly enhances the rate and yield of the
      folding reaction and suppresses non-productive reaction cycles (PMID:30955883).
      The client repertoire extends beyond cytoskeletal proteins to include the VHL
      tumor suppressor, where prefoldin prevents pVHL aggregation and degradation
      (DOI:10.1371/journal.pgen.1009183). A 2024 DIP-MS study resolved canonical and
      alternative prefoldin assemblies, suggesting context-specific modular complex
      organization (DOI:10.1038/s41592-024-02211-y).
    molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005737
        label: cytoplasm
    in_complex:
      id: GO:0016272
      label: prefoldin complex
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: >-
          We describe the discovery of a heterohexameric chaperone protein, prefoldin,
          based on its ability to capture unfolded actin. Prefoldin binds specifically
          to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
      - reference_id: PMID:30955883
        supporting_text: >-
          PFD can act after TRiC bound its substrates to enhance the rate and yield
          of the folding reaction, suppressing non-productive reaction cycles.

PFDN1

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

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