PFDN5

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: GO:0005737 "cytoplasm" is a well-supported cellular component annotation for PFDN5. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from yeast (SGD:S000001871, SGD:S000004559), Arabidopsis, and human PFDN5 itself. 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). 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. Having both is correct: one describes the subcellular location and the other describes complex membership. Reason: PFDN5 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). Consistent with PFDN1 review. 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:1990113 RNA polymerase I assembly	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GO:1990113 "RNA polymerase I assembly" is an IBA annotation inferred from phylogenetic analysis (PANTHER:PTN000293176) with evidence from yeast (SGD:S000001871). In yeast, prefoldin subunits have been shown to participate in the assembly of RNA polymerases I, II, and III. Tahmaz et al. 2022 describe that "canonical prefoldin contributes to transcription elongation" and has roles in nuclear gene expression control. This function is conserved across eukaryotes per phylogenetic inference and is consistent with the known nuclear localization of PFDN5 isoforms MM-1alpha and MM-1gamma (PMID:32699605). This represents a nuclear, non-core function distinct from the primary cytoplasmic chaperone role. Reason: RNA polymerase I assembly is a secondary function for PFDN5, distinct from its core cytoplasmic co-chaperone role. The IBA phylogenetic inference from yeast (SGD:S000001871) is reasonable, and prefoldin subunits have documented nuclear roles in transcription-related processes. However, this is not the primary function of PFDN5 in humans. Supporting Evidence: PMID:32699605 MM-1β and MM-1δ are mainly localized in the cytoplasm, while MM-1α and MM-1γ are localized in the nucleus, and MM1 isoforms that bind to c-Myc and TIF1β are located in the nucleus [101].
GO:1990114 RNA polymerase II core complex assembly	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GO:1990114 "RNA polymerase II core complex assembly" is an IBA annotation inferred from phylogenetic analysis (PANTHER:PTN000293176) with evidence from yeast (SGD:S000001871). In yeast, prefoldin subunits contribute to RNA polymerase II assembly. This function is consistent with the known nuclear localization of PFDN5 isoforms and the broader role of prefoldin in transcription-related processes. However, this is a secondary function for PFDN5 in humans, distinct from its core cytoplasmic chaperone role. Reason: RNA polymerase II assembly is a secondary function for PFDN5, supported by phylogenetic inference from yeast. While prefoldin subunits have documented roles in nuclear transcription processes, this is not the primary function of PFDN5 in humans, where its core role is as a cytoplasmic co-chaperone.
GO:1990115 RNA polymerase III assembly	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GO:1990115 "RNA polymerase III assembly" is an IBA annotation inferred from phylogenetic analysis (PANTHER:PTN000293176) with evidence from yeast (SGD:S000001871). In yeast, prefoldin subunits contribute to RNA polymerase III assembly. This function is consistent with the nuclear roles of prefoldin subunits but represents a secondary function for PFDN5 in humans. Reason: RNA polymerase III assembly is a secondary function for PFDN5, supported by phylogenetic inference from yeast. Not the core function of PFDN5 in humans.
GO:0016272 prefoldin complex	IBA GO_REF:0000033	ACCEPT	Summary: GO:0016272 "prefoldin complex" is a core cellular component annotation for PFDN5. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from Drosophila (FB:FBgn0038976), yeast (SGD:S000004559), Arabidopsis, and human PFDN5. PFDN5 is one of the two alpha subunits (PFDN3 and PFDN5) of the heterohexameric prefoldin complex (PMID:9630229, PMID:30955883). The complex is registered in ComplexPortal as CPX-6149 and CPX-25767. Liang et al. 2020 (PMID:32699605) confirm: "Eukaryotic prefoldin complex is a heterohexameric complex like a jellyfish-like structure, consisting of six different subunits (PFDN1-6): two alpha subunits (PFDN3 and PFDN5) and four beta subunits." Reason: PFDN5 is a core structural alpha subunit of the prefoldin complex. The IBA annotation is phylogenetically well-supported and consistent with extensive experimental evidence from cryo-EM structural studies (PMID:30955883) and reconstitution experiments (PMID:23614719). Supporting Evidence: PMID:32699605 Eukaryotic prefoldin complex is a heterohexameric complex like a jellyfish-like structure, consisting of six different subunits (PFDN1–6): two α subunits (PFDN3 and PFDN5) and four β subunits (PFDN1, PFDN2, PFDN4, and PFDN6) [8] PMID:30955883 Maintaining proteostasis in eukaryotic protein folding involves cooperation of distinct chaperone systems.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: GO:0005634 "nucleus" inferred electronically from UniProtKB subcellular location vocabulary mapping. UniProt records isoform-specific localization: isoform 1 (MM-1alpha) and isoform 3 (MM-1gamma) localize to the nucleus, while isoform 2 (MM-1beta) is cytoplasmic. Liang et al. 2020 (PMID:32699605) confirm: "MM-1alpha and MM-1gamma are localized in the nucleus." The nuclear localization is consistent with the moonlighting function of PFDN5/MM-1 as a c-Myc transcriptional corepressor (PMID:9792694). This IEA annotation is correct and consistent with the TAS annotation from PMID:9792694. Reason: Nuclear localization of PFDN5 is well-established for the MM-1alpha and MM-1gamma isoforms. The IEA mapping from UniProt subcellular location is correct and consistent with the c-Myc corepressor function (PMID:9792694, PMID:32699605). Supporting Evidence: PMID:32699605 MM-1β and MM-1δ are mainly localized in the cytoplasm, while MM-1α and MM-1γ are localized in the nucleus, and MM1 isoforms that bind to c-Myc and TIF1β are located in the nucleus [101].
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: GO:0005737 "cytoplasm" inferred electronically from UniProtKB subcellular location vocabulary mapping. UniProt records that isoform 2 (MM-1beta) localizes to the cytoplasm. The prefoldin complex operates primarily in the cytoplasm for its co-chaperone function (PMID:9630229, PMID:32699605). This IEA annotation is consistent with the IBA annotation to the same term and is correct. Reason: Cytoplasmic localization is correct for PFDN5 -- both for the canonical prefoldin complex function and for the MM-1beta isoform specifically. Consistent with the IBA annotation and experimental evidence.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: GO:0006457 "protein folding" inferred electronically from InterPro domain mapping (IPR011599, the prefoldin alpha-type domain). This IEA annotation is consistent with the IDA and NAS annotations to the same term, and with the well-established role of the prefoldin complex in protein folding (PMID:9630229, PMID:30955883). Reason: The IEA annotation to protein folding via InterPro is correct and consistent with the higher-confidence IDA and NAS annotations. The prefoldin alpha domain (IPR011599) 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 (IPR011599, the prefoldin alpha domain). PFDN5 is one of the two alpha subunits of the heterohexameric prefoldin complex (PMID:9630229, PMID:32699605). This IEA annotation is consistent with the IBA and IDA annotations to the same term. Reason: PFDN5 is a core structural subunit of the prefoldin complex. The IEA mapping from the prefoldin alpha domain (IPR011599) 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 -- PFDN5 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 from IBA, IEA, and IDA evidence. The term "protein-containing complex" adds no informational value. Reason: This is an overly general annotation. PFDN5 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 IBA, IEA, and IDA evidence. The generic "protein-containing complex" adds no useful information. Consistent with PFDN1 review decision.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). This IEA annotation was inferred electronically from InterPro domain mapping (IPR011599, the prefoldin alpha domain). 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 (PMID:9630229). The more appropriate term is GO:0044183 "protein folding chaperone" which captures the functional chaperone activity rather than just substrate binding. Consistent with PFDN1 review. Reason: GO:0051082 is now formally obsolete. The term describes only a binding activity and does not capture the chaperone function of prefoldin. 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 (PMID:9630229, PMID:30955883). 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 can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles.
GO:0005515 protein binding	IPI PMID:17728244 Stimulation of c-Myc transcriptional activity by vIRF-3 of K...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9DUN1/vIRF-3) from PMID:17728244, a study on Kaposi sarcoma-associated herpesvirus vIRF-3 stimulation of c-Myc transcriptional activity. The UniProt record confirms this interaction (NbExp=8). This is a viral-host interaction where vIRF-3 interacts with PFDN5/MM-1 to modulate c-Myc activity. While the interaction may be biologically relevant in the context of viral infection, "protein binding" is uninformative as an annotation for the host protein PFDN5. Reason: "Protein binding" is uninformative. While the PFDN5-vIRF-3 interaction is supported by multiple experiments and is relevant to viral manipulation of the c-Myc pathway, the GO term provides no functional insight. The transcriptional corepressor function is better captured by GO:0003714.
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q13137/CALCOCO2) from PMID:21516116, a next-generation sequencing study to generate interactome datasets. This is a high-throughput interaction study. The biological significance of a PFDN5-CALCOCO2 interaction is unclear. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. This high-throughput interaction screen detection does not provide functional insight. The core functions of PFDN5 are already captured by more specific annotations.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:O14775/GNB5, UniProtKB:P62873/GNB1, UniProtKB:Q9NYS7/WSB2, UniProtKB:Q9UHV9/PFDN2) from PMID:25036637, a quantitative chaperone interaction network study. The PFDN5-PFDN2 interaction is expected since both are subunits of the prefoldin complex (UniProt records NbExp=8 for this interaction). The other interactions are from a large-scale chaperone network study. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. The PFDN5-PFDN2 interaction is already captured by prefoldin complex membership (GO:0016272). The other interactions detected in the chaperone network study do not provide functional insight beyond what is captured by GO:0044183 and GO:0016272.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:O76003/GLRX3, UniProtKB:P61289/PSME3, UniProtKB:Q13137/CALCOCO2, UniProtKB:Q9UKT9/IKZF3) from PMID:25416956, a proteome-scale map of the human interactome network. These are high-throughput interactions. The PFDN5-PSME3 interaction (NbExp=6 in UniProt) could reflect a connection between prefoldin and proteasome regulation, consistent with the known role of PFDN5/MM-1 in promoting c-Myc proteasomal degradation. However, "protein binding" remains uninformative. Reason: "Protein binding" is uninformative. While some interactions (e.g., PSME3) may relate to the proteasome-mediated c-Myc degradation function of PFDN5, the GO term itself provides no functional insight. The core functions are captured by more specific terms.
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:P61758/VBP1, UniProtKB:Q9UHV9/PFDN2) from Huttlin et al. 2017 (PMID:28514442), the BioPlex human interactome study. The PFDN5-PFDN2 interaction (NbExp=8) and PFDN5-VBP1 interaction (NbExp=9) reflect prefoldin complex subunit and prefoldin-like complex interactions. VBP1 (von Hippel-Lindau binding protein 1) is a prefoldin-like protein. These interactions are already captured by GO:0016272. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. The PFDN5-PFDN2 and PFDN5-VBP1 interactions reflect co-membership in prefoldin/prefoldin-like complexes, already captured by GO:0016272. The BioPlex study does not add functional insight beyond complex membership.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9UKT9/IKZF3) from PMID:31515488, a study on extensive disruption of protein interactions by genetic variants. The PFDN5-IKZF3 interaction (NbExp=7 in UniProt) has been detected in multiple studies. IKZF3/Aiolos is a transcription factor, and this interaction could relate to PFDN5's transcriptional regulatory functions. However, "protein binding" is uninformative. Reason: "Protein binding" is uninformative. While the PFDN5-IKZF3 interaction has been detected multiple times, the GO term provides no functional insight.
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 numerous interactors) from Luck et al. 2020 (PMID:32296183), a reference map of the human binary protein interactome (HuRI). This study detected a very large number of interactions for PFDN5, including with other prefoldin subunits (PFDN2, VBP1), transcription factors, and many other proteins. While the large number of interactions may partly reflect the coiled-coil structure of PFDN5, "protein binding" is uninformative as a GO annotation. Reason: "Protein binding" is uninformative. This large-scale binary interactome study detected many interactions for PFDN5, but the GO term provides no functional insight. The core molecular functions of PFDN5 are already captured by GO:0044183 (protein folding chaperone) and GO:0003714 (transcription corepressor activity).
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:O14901/KLF11, UniProtKB:P42858/HTT, UniProtKB:Q7Z412/PEX26) from PMID:32814053, an interactome mapping study for neurodegenerative disease proteins. The PFDN5-HTT (Huntingtin) interaction is biologically interesting given prefoldin's role in preventing Huntingtin protein aggregation (PMID:32699605). However, "protein binding" remains uninformative. Reason: "Protein binding" is uninformative. While the PFDN5-HTT interaction may be relevant to prefoldin's neuroprotective role, the GO term provides no functional insight.
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:O14775/GNB5, UniProtKB:P61758/VBP1, UniProtKB:P62873/GNB1, UniProtKB:Q9UHV9/PFDN2) from Huttlin et al. 2021 (PMID:33961781), a dual proteome-scale network study. These are replications of previously observed interactions. The PFDN5-PFDN2 and PFDN5-VBP1 interactions reflect prefoldin complex membership. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. These are replications of previously observed interactions 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:P62873/GNB1, UniProtKB:Q9NYS7/WSB2, UniProtKB:Q9UHV9/PFDN2) from multimodal cell maps study (PMID:40205054). This is a further replication of known interactions. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. These are further replications of known interactions. The relevant functions are already captured by more specific annotations (GO:0044183, GO:0016272).
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: GO:0005829 "cytosol" (IDA) from the Human Protein Atlas, based on curation of immunofluorescence data. The prefoldin complex operates in the cytosol for its co-chaperone function, binding nascent polypeptides and delivering them to TRiC/CCT (PMID:9630229). This is consistent with the IBA annotation to "cytoplasm" (GO:0005737) and provides a more specific localization. The cytosolic localization is expected for the canonical chaperone function of PFDN5 as part of the prefoldin complex. Reason: Cytosol localization is well-supported by immunofluorescence data and is consistent with the cytoplasmic co-chaperone function of the prefoldin complex. This provides a more specific localization than the broader "cytoplasm" annotation.
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 IDA annotations to the same term and is well-supported by the review literature. Reason: Protein folding is the core biological process for PFDN5 as part of the prefoldin complex. This NAS annotation from ComplexPortal cites a well-sourced review (PMID:32699605) that accurately describes the protein folding function. 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 IDA annotations and is well-supported. Reason: Protein folding is the core biological process for PFDN5. This NAS annotation from ComplexPortal cites a comprehensive review (PMID:34761191) that accurately describes the co-chaperone function of prefoldin subunits. 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 but mischaracterizes the nature of the chaperone activity. Consistent with PFDN1 review. 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. The core process (protein folding, GO:0006457) is already well-annotated with 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." 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 PFDN5. 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 PFDN5) and characterized its structure and function through cryo-EM, crosslinking mass spectrometry, and biochemical assays. The cryo-EM structures (PDB: 6NR8, 6NR9, 6NRB, 6NRC, 6NRD) include PFDN5 as chain 5. This provides direct structural evidence for PFDN5 membership in the prefoldin complex. Reason: PFDN5 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 PFDN5 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 now formally obsolete (go-ontology#30962). This IDA annotation cites Gestaut et al. 2019 (PMID:30955883), which demonstrated that prefoldin associates with TRiC through a conserved electrostatic interface and undergoes conformational cycling between "latched" (open) and "engaged" (closed) states during substrate transfer. The paper shows that PFD functions not merely as a passive binder of unfolded substrates but as an active co-chaperone. GO:0044183 "protein folding chaperone" is the appropriate replacement. Consistent with PFDN1 review. Reason: GO:0051082 is now formally obsolete. Gestaut et al. 2019 (PMID:30955883) demonstrates that prefoldin functions as a co-chaperone/holdase that cooperates with TRiC/CCT, not merely as an unfolded protein binder. GO:0044183 "protein folding chaperone" accurately describes this co-chaperone activity. The GO:0044183 definition ("Binding to a protein or a protein-containing complex to assist the protein folding process") appropriately encompasses the holdase/transfer 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 PFD alternates between an open "latched" conformation and a closed "engaged" conformation that aligns the PFD-TRiC substrate binding chambers. PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
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 PFDN5 -- it reflects the general chaperone/holdase property of prefoldin applied to an amyloidogenic substrate. The annotation was made on the intact prefoldin complex, not PFDN5 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 PFDN5. While the data are solid, this represents a peripheral function compared to the core role in actin/tubulin folding via TRiC/CCT delivery. Consistent with PFDN1 review. 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 PFDN5 provides direct evidence for PFDN5 membership in the prefoldin complex. This is consistent with the IDA annotation from PMID:30955883 and the IBA/IEA annotations. Reason: PFDN5 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. The study was performed on the intact hexameric complex, not PFDN5 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. Consistent with PFDN1 review. 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:0045892 negative regulation of DNA-templated transcription	IMP PMID:18281035 Negative regulation of the Wnt signal by MM-1 through inhibi...	KEEP AS NON CORE	Summary: GO:0045892 "negative regulation of DNA-templated transcription" (IMP) from PMID:18281035, annotated by BHF-UCL. PFDN5/MM-1 is well-established as a transcriptional corepressor of c-Myc. Mori et al. 1998 (PMID:9792694) originally identified MM-1 as "a novel c-Myc-associating protein that represses transcriptional activity of c-Myc." Liang et al. 2020 (PMID:32699605) describe multiple regulatory mechanisms including inhibition of c-Myc E-box-dependent transcriptional activity via TIF1beta/HDAC-mSin3 recruitment. This is a well-supported moonlighting function of PFDN5 that is independent of its prefoldin complex chaperone role. Reason: Negative regulation of transcription is a well-supported moonlighting function of PFDN5/MM-1, independent of its core cytoplasmic co-chaperone role. The c-Myc corepressor function is mediated by nuclear isoforms (MM-1alpha, MM-1gamma) and involves recruitment of TIF1beta/HDAC-mSin3 corepressor complex (PMID:9792694, PMID:32699605). Classified as non-core because the primary function of PFDN5 as a prefoldin subunit is protein folding chaperone activity. Supporting Evidence: PMID:32699605 (c)MM-1 inhibits the E-box-dependent transcriptional activity of c-Myc by recruiting a histone deacetylase (HDAC-mSin3) complex from TIF1β/KAP1/TRIM28 (a transcriptional co-inhibitor) (Fig
GO:0090090 negative regulation of canonical Wnt signaling pathway	IMP PMID:18281035 Negative regulation of the Wnt signal by MM-1 through inhibi...	KEEP AS NON CORE	Summary: GO:0090090 "negative regulation of canonical Wnt signaling pathway" (IMP) from PMID:18281035, annotated by BHF-UCL. Liang et al. 2020 (PMID:32699605) describe this mechanism: MM-1 negatively regulates the expression of wnt4 by binding to Egr-1, thereby indirectly inhibiting c-Myc expression. This represents one of the multiple mechanisms by which PFDN5/MM-1 inhibits c-Myc activity. This is part of the moonlighting transcriptional regulatory function of PFDN5. Reason: Negative regulation of Wnt signaling is part of the moonlighting transcriptional regulatory function of PFDN5/MM-1. It represents one of the multiple mechanisms by which MM-1 inhibits c-Myc activity (PMID:32699605). This is a secondary function compared to the core co-chaperone role. Supporting Evidence: PMID:32699605 MM-1 negatively regulates the expression of wnt4 by binding to Egr-1, thereby indirectly inhibiting c-Myc expression (Fig
GO:0005737 cytoplasm	TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	ACCEPT	Summary: GO:0005737 "cytoplasm" (TAS) from PMID:16130169, a proteomics study of human umbilical vein endothelial cells. This study identified PFDN5 in the proteome of HUVECs, consistent with its cytoplasmic localization. The cytoplasmic localization is well-established for the prefoldin complex (PMID:9630229, PMID:32699605) and is consistent with the IBA and IEA annotations to the same term. Reason: Cytoplasmic localization is well-supported and consistent with the canonical co-chaperone function of the prefoldin complex. This TAS annotation is consistent with multiple other annotations to the same term.
GO:0003714 transcription corepressor activity	TAS PMID:9792694 MM-1, a novel c-Myc-associating protein that represses trans...	KEEP AS NON CORE	Summary: GO:0003714 "transcription corepressor activity" (TAS) from PMID:9792694, the original paper by Mori et al. 1998 that identified MM-1 as "a novel c-Myc-associating protein that represses transcriptional activity of c-Myc." UniProt confirms: "Represses the transcriptional activity of MYC." Liang et al. 2020 (PMID:32699605) describe multiple corepressor mechanisms including recruitment of HDAC-mSin3 complex via TIF1beta/KAP1/TRIM28, proteasomal degradation of c-Myc via Rabring7, and suppression of Wnt4 via Egr-1. This is a well-characterized moonlighting function of PFDN5/MM-1 that is distinct from and independent of its prefoldin complex chaperone role. Reason: Transcription corepressor activity is a well-established moonlighting function of PFDN5/MM-1, distinct from the core cytoplasmic co-chaperone role. It is mediated specifically by the nuclear isoforms (MM-1alpha, MM-1gamma) and involves binding to the MBII region of c-Myc's N-terminal domain and recruitment of TIF1beta/HDAC-mSin3 corepressor complex (PMID:9792694, PMID:32699605). While this is an important biological function, the primary identity of PFDN5 is as a prefoldin subunit, so this is classified as non-core. Supporting Evidence: PMID:32699605 MM-1 is one of the c-Myc NTD-terminated proteins which is bound to the MBII region of the NTD and can compete with TRRAP for c-Myc [99]. PMID:32699605 MM1, a nuclear c-Myc binding protein, inhibits c-Myc activity in the nucleus in various ways and is therefore considered a tumor suppressor.
GO:0005634 nucleus	TAS PMID:9792694 MM-1, a novel c-Myc-associating protein that represses trans...	ACCEPT	Summary: GO:0005634 "nucleus" (TAS) from PMID:9792694, the original paper by Mori et al. 1998 that identified MM-1. The nuclear localization of PFDN5/MM-1 is well-established for the MM-1alpha and MM-1gamma isoforms, which bind c-Myc and function as transcriptional corepressors in the nucleus (PMID:32699605). Consistent with the IEA annotation to the same term from GO_REF:0000044. Reason: Nuclear localization is well-supported for PFDN5 isoforms MM-1alpha and MM-1gamma. This is consistent with the moonlighting transcriptional corepressor function (PMID:9792694, PMID:32699605) and the IEA annotation. Supporting Evidence: PMID:32699605 MM-1β and MM-1δ are mainly localized in the cytoplasm, while MM-1α and MM-1γ are localized in the nucleus, and MM1 isoforms that bind to c-Myc and TIF1β are located in the nucleus [101].
GO:0006355 regulation of DNA-templated transcription	TAS PMID:9792694 MM-1, a novel c-Myc-associating protein that represses trans...	KEEP AS NON CORE	Summary: GO:0006355 "regulation of DNA-templated transcription" (TAS) from PMID:9792694. This is a broad parent term that encompasses the more specific GO:0045892 "negative regulation of DNA-templated transcription" already annotated with IMP evidence from PMID:18281035. PFDN5/MM-1 is well-established as a transcriptional regulator through its c-Myc corepressor function. However, this term is redundant with the more specific GO:0045892 annotation. The annotation should be modified to the more specific child term or kept as-is since GO:0045892 already exists. Reason: Regulation of transcription is well-supported for PFDN5/MM-1 through its c-Myc corepressor function (PMID:9792694, PMID:32699605). While this term is broader than the existing GO:0045892 annotation, it is not wrong -- PFDN5 does regulate transcription. This is a secondary/moonlighting function. The more specific GO:0045892 from PMID:18281035 provides better resolution. Supporting Evidence: PMID:32699605 MM1, a nuclear c-Myc binding protein, inhibits c-Myc activity in the nucleus in various ways and is therefore considered a tumor suppressor.
GO:0044183 protein folding chaperone	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	NEW	Summary: GO:0044183 "protein folding chaperone" is the most appropriate molecular function term for PFDN5 as a prefoldin subunit. This annotation is proposed as a manual NEW entry supported by direct experimental evidence from Gestaut et al. 2019. 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. This term is also the recommended replacement for the obsoleting GO:0051082 "unfolded protein binding." Reason: GO:0044183 "protein folding chaperone" is the core molecular function of PFDN5 as a prefoldin subunit. The prefoldin complex is a bona fide protein folding chaperone that captures unfolded substrates and delivers them to TRiC/CCT (PMID:9630229, PMID:30955883). This term should be added to PFDN5 to replace the obsoleting GO:0051082. 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. file:human/PFDN5/PFDN5-deep-research-falcon.md Cytosolic co-chaperone: Prefoldin binds nascent actin and tubulin, prevents aggregation, and transfers clients to TRiC/CCT, accelerating folding efficiency.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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