VBP1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: GO:0005737 "cytoplasm" is an appropriate cellular component annotation for VBP1. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from Drosophila (FB:FBgn0264694), yeast (SGD:S000003310), Arabidopsis, C. elegans, and human VBP1 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 subcellular location and the other describes complex membership. Reason: VBP1 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:0007017 microtubule-based process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: GO:0007017 "microtubule-based process" is a well-supported biological process annotation for VBP1. This IBA annotation was inferred from phylogenetic analysis (PANTHER) with evidence from Drosophila and Arabidopsis orthologs. The prefoldin complex delivers unfolded tubulin to TRiC/CCT for folding, and loss of prefoldin subunits disrupts microtubule dynamics and cytoskeletal homeostasis (PMID:9630229). Vainberg et al. 1998 showed that "Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results in a phenotype similar to those found when c-cpn is mutated, namely impaired functions of the actin and tubulin-based cytoskeleton." This is a direct consequence of the prefoldin chaperone function rather than a core process per se, but it is a well-established downstream effect. Reason: Microtubule-based process is a well-established downstream consequence of prefoldin's role in tubulin folding, but it is not the core process directly executed by VBP1. The more precise core biological process is tubulin complex assembly (GO:0007021); this broader term can be retained as a non-core downstream consequence. Supporting Evidence: PMID:9630229 Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results in a phenotype similar to those found when c-cpn is mutated, namely impaired functions of the actin and tubulin-based cytoskeleton.
GO:0016272 prefoldin complex	IBA GO_REF:0000033	ACCEPT	Summary: GO:0016272 "prefoldin complex" is an unambiguous and well-supported CC annotation. VBP1 (PFDN3) is one of the two alpha subunits of the heterohexameric prefoldin complex (PMID:9630229, PMID:32699605). This IBA annotation was inferred from phylogenetic analysis with evidence from Drosophila, yeast, and human VBP1 itself. Structural data from cryo-EM (PMID:30955883, PDB: 6NR8, 7WU7) directly shows VBP1 as a structural component of the human prefoldin complex. The complex is also registered in ComplexPortal as CPX-6149 and CPX-25767. Reason: VBP1 is a core structural alpha subunit of the prefoldin complex. This is the defining complex membership for VBP1. The IBA annotation is phylogenetically well-supported and confirmed by multiple independent experimental studies (PMID:9630229, PMID:30955883, PMID:23614719). Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. 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:0007021 tubulin complex assembly	IBA GO_REF:0000033	ACCEPT	Summary: GO:0007021 "tubulin complex assembly" is supported by the canonical function of the prefoldin complex. This IBA annotation was inferred from phylogenetic analysis with evidence from yeast (SGD:S000003310). The prefoldin complex captures nascent tubulin monomers and delivers them to TRiC/CCT for folding, which is a prerequisite for tubulin heterodimer assembly (PMID:9630229). Vainberg et al. 1998 showed prefoldin promotes tubulin folding, and deletion of prefoldin subunit genes in yeast results in impaired tubulin-based cytoskeleton function. This is a core function of all prefoldin subunits. Reason: Tubulin complex assembly is a direct consequence of the prefoldin complex's chaperone function in delivering unfolded tubulin to TRiC/CCT. The IBA annotation is phylogenetically well-supported (PMID:9630229). 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. file:human/VBP1/VBP1-deep-research-falcon.md VBP1 encodes the α-type prefoldin subunit 3, a component of the heterohexameric prefoldin cochaperone that captures nascent polypeptides—most prominently actin and tubulin monomers—and delivers them to the TRiC/CCT chaperonin for ATP-dependent folding.
GO:0015631 tubulin binding	IBA GO_REF:0000033	ACCEPT	Summary: GO:0015631 "tubulin binding" reflects the canonical substrate specificity of the prefoldin complex. This IBA annotation was inferred from phylogenetic analysis with evidence from Drosophila and yeast. The prefoldin complex binds unfolded tubulin monomers and delivers them to TRiC/CCT (PMID:9630229). However, tubulin binding is a consequence of the broader protein folding chaperone function, and the prefoldin complex also binds actin and other substrates including VHL. The annotation is correct but represents a substrate specificity rather than a mechanistic function. Reason: Tubulin binding is a well-established substrate specificity of the prefoldin complex. The IBA annotation is phylogenetically well-supported and consistent with the seminal characterization of prefoldin (PMID:9630229). While somewhat reductionist (prefoldin also binds actin and other substrates), tubulin is one of the primary substrates and this annotation captures an important specificity. Supporting Evidence: PMID:9630229 Deletion of the gene encoding a prefoldin subunit in S. cerevisiae results in a phenotype similar to those found when c-cpn is mutated, namely impaired functions of the actin and tubulin-based cytoskeleton.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: GO:0005634 "nucleus" was inferred electronically from the UniProt subcellular location annotation for VBP1. The UniProt record states "Cytoplasm. Nucleus. Note=In complex with VHL can translocate to the nucleus." The cached direct support is the original VBP1/VHL paper, which reports cytoplasmic localization when VBP1 is expressed alone and VHL-dependent nuclear translocation (PMID:8674032). This is a context-dependent localization, not the primary site of VBP1 prefoldin chaperone activity. Reason: VBP1 can translocate to the nucleus in complex with VHL, but its core role is as a cytosolic prefoldin subunit delivering actin/tubulin substrates to TRiC/CCT. Keep the nuclear localization as a non-core, context-dependent localization. Supporting Evidence: PMID:8674032 When the VBP-1 protein was solely expressed, it located to the cytoplasm and did not localize to the nucleus. However, when coexpressed with VHL, it can translocate to the nucleus.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: GO:0005737 "cytoplasm" was inferred electronically by the combined automated annotation pipeline. This is consistent with the IBA annotation to the same term and the well-established cytoplasmic localization of the prefoldin complex (PMID:9630229, PMID:32699605). Reason: Cytoplasm is the primary site of prefoldin chaperone activity. This IEA annotation is consistent with higher-confidence IBA and TAS annotations to the same term.
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: GO:0006457 "protein folding" was inferred electronically from InterPro domain mapping (IPR016655, the PFD3/prefoldin subunit 3 domain). This IEA annotation is consistent with 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 higher-confidence IDA and NAS annotations. The PFD3 domain (IPR016655) 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" was inferred electronically from InterPro domain mapping (IPR016655, the PFD3 domain). VBP1 (PFDN3) is one of the two alpha subunits of the heterohexameric prefoldin complex (PMID:9630229, PMID:32699605). This IEA annotation is consistent with IBA and IDA annotations to the same term from PMID:30955883 and PMID:23614719. Reason: VBP1 is a core structural subunit of the prefoldin complex. The IEA mapping from the PFD3 domain (IPR016655) 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 -- VBP1 is part of the prefoldin complex, which is 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. Reason: This is an overly general annotation. VBP1 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.
GO:0005515 protein binding	IPI PMID:17698809 von Hippel Lindau binding protein 1-mediated degradation of ...	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:P35963/HIV-1 gag-pol polyprotein) from an IntAct interaction study (PMID:17698809). This interaction between VBP1 and the HIV-1 integrase/gag-pol context reflects a focused mechanism in which VBP1 bridges HIV-1 integrase to the Cul2/VHL ubiquitin ligase for degradation. This viral integrase/VHL-proteasome context is not the core prefoldin function, and "protein binding" is an uninformative GO term that does not describe a specific molecular function. Reason: "Protein binding" is uninformative. The cited paper describes a non-core viral integrase/VHL/Cul2 degradation mechanism rather than a generic high-throughput hit or the core prefoldin chaperone function. The core molecular function of VBP1 is better captured by GO:0044183 "protein folding chaperone."
GO:0005515 protein binding	IPI PMID:22190034 Global landscape of HIV-human protein complexes.	MARK AS OVER ANNOTATED	Summary: GO:0005515 "protein binding" (IPI with UniProtKB:Q9Q2G4/viral ORF) from Jager et al. 2012 (PMID:22190034), a study mapping the global landscape of HIV-human protein complexes. The interaction between VBP1 and a viral protein was identified in this high-throughput study. "Protein binding" is an uninformative GO term. Reason: "Protein binding" is uninformative. This high-throughput HIV-host interactome screen detection does not provide functional insight for VBP1. The core molecular function is already captured by more specific terms.
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:Q8ND90/PNMA1, Q96S82/UBL7, Q9NQP4/PFDN4) from Rolland et al. 2014 (PMID:25416956), a proteome-scale map of the human interactome network. The interaction with PFDN4 reflects intra-complex interactions expected for prefoldin subunits. The interactions with PNMA1 and UBL7 are from a large-scale Y2H screen. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. The VBP1-PFDN4 interaction reflects co-membership in the prefoldin complex (already captured by GO:0016272). The other interactions are from high-throughput screens and do not provide functional insight.
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:Q96S82/UBL7, Q99471/PFDN5, Q9NQP4/PFDN4, Q9UHV9/PFDN2) from Huttlin et al. 2017 (PMID:28514442), the BioPlex human interactome study. The interactions with PFDN2, PFDN4, and PFDN5 are expected intra-complex interactions since all are subunits of the prefoldin hexamer. The UBL7 interaction is from a large-scale screen. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. The interactions with PFDN2, PFDN4, and PFDN5 reflect co-membership in the prefoldin complex, already captured by GO:0016272. High-throughput interactome data does not add 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 many partners including PFDN2, PFDN4, PFDN5, and numerous other proteins) from Luck et al. 2020 (PMID:32296183), a reference map of the human binary protein interactome (HuRI). This study detected numerous interactions for VBP1 in a large-scale Y2H screen. The prefoldin subunit interactions are expected. The many other interactions (with transcription factors, kinases, etc.) may reflect the broad substrate recognition capacity of prefoldin or may be false positives in a high-throughput screen. "Protein binding" is uninformative in all cases. Reason: "Protein binding" is uninformative. This is a large-scale interactome study with many detected partners. The prefoldin subunit interactions are already captured by GO:0016272. The non-prefoldin interactions do not provide functional insight and the generic GO term adds no value.
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 multiple partners including PFDN2 and various other proteins) from Metzger et al. 2020 (PMID:32814053), an interactome mapping study of neurodegenerative disease proteins. The interaction with PFDN2 is expected as both are prefoldin subunits. The other interactions are from a high-throughput screen focused on neurodegeneration-related proteins. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. The PFDN2 interaction reflects prefoldin complex membership (GO:0016272). The other high-throughput interactions do not provide functional insight. The core molecular function is already captured by more specific terms.
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:Q96S82/UBL7, Q99471/PFDN5, Q9NQP4/PFDN4, Q9UHV9/PFDN2) from Huttlin et al. 2021 (PMID:33961781), a dual proteome-scale network study. This confirms previously observed interactions: the intra-prefoldin subunit interactions (PFDN2, PFDN4, PFDN5) and UBL7. "Protein binding" remains uninformative. Reason: "Protein binding" is uninformative. These are replications of previously observed interactions (intra-prefoldin complex; UBL7) that do not add functional insight beyond what is captured by GO:0016272 (prefoldin complex).
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:Q9NQP4/PFDN4 and Q9UHV9/PFDN2) from multimodal cell maps study (PMID:40205054). This is yet another replication of VBP1-PFDN2 and VBP1-PFDN4 intra-complex interactions. "Protein binding" is uninformative. Reason: "Protein binding" is uninformative. This is a further replication of known intra-prefoldin complex interactions from a large-scale study. The relevant functions are already captured by GO:0016272 (prefoldin complex).
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: GO:0005829 "cytosol" was annotated by the Human Protein Atlas (HPA) based on curation of immunofluorescence data (GO_REF:0000052). The prefoldin complex operates primarily in the cytosol to capture unfolded nascent polypeptides and deliver them to TRiC/CCT (PMID:9630229). This is a more specific subcellular localization than "cytoplasm" (GO:0005737) and is consistent with the known biology. Cytosol is a child of cytoplasm. Reason: Cytosol localization is well-supported by the known biology of the prefoldin complex operating in the cytosol to deliver substrates to TRiC/CCT. The HPA immunofluorescence data provides direct evidence. This is a more specific and informative term than the broader "cytoplasm" annotation. Supporting Evidence: PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
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 IBA and IDA annotations to the same term and is well-supported. Reason: Protein folding is the core biological process for VBP1. 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 IDA evidence from PMID:30955883. 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 IDA and IBA annotations to the same term. Reason: Protein folding is the core biological process for VBP1. This NAS annotation from ComplexPortal cites a comprehensive review (PMID:34761191) that accurately describes the co-chaperone function of prefoldin subunits. Consistent with IDA evidence from PMID:30955883. 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). For VBP1 specifically, there is additional evidence that prefoldin/VBP1 prevents pVHL aggregation and supports its maturation (deep research: Le Goff et al. 2016, Tahmaz et al. 2022). However, "protein stabilization" typically implies maintaining a folded protein in its native state, whereas prefoldin acts primarily on unfolded nascent polypeptides as a holdase. The term is not entirely wrong but mischaracterizes the primary chaperone activity. Reason: While prefoldin does prevent protein aggregation (which is part of the GO definition of protein stabilization), and VBP1/prefoldin specifically helps prevent pVHL aggregation, the primary function is to capture unfolded substrates and transfer them to TRiC/CCT for folding. "Protein stabilization" represents a secondary aspect rather than the core activity. The core process (protein folding, GO:0006457) is already well-annotated. 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 including VBP1. 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 VBP1. 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 VBP1/PFDN3 and characterized its structure through cryo-EM and crosslinking mass spectrometry. The study resolved the architecture of the PFD-TRiC supra-chaperone complex, directly demonstrating that VBP1 is a component of the prefoldin complex. The cryo-EM structures (PDB: 6NR8, 6NR9, 6NRB, 6NRC, 6NRD) include VBP1 as chain 3. Reason: VBP1 is a core structural alpha 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 VBP1 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 that enhances folding rates. GO:0044183 "protein folding chaperone" (defined as "Binding to a protein or a protein-containing complex to assist the protein folding process") is the appropriate replacement, capturing the functional holdase/transfer chaperone role. 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 in substrate folding, not merely as an unfolded protein binder. GO:0044183 "protein folding chaperone" accurately describes the co-chaperone activity of VBP1 as part of the prefoldin complex. 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: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. Thioflavin T measurements and immunoblotting showed that hPFD directly interacts with Abeta peptides. While this demonstrates that the prefoldin complex can bind Abeta, this is not the core function of VBP1 -- it reflects the general chaperone/holdase property of prefoldin applied to an amyloidogenic substrate. The annotation was made on the intact prefoldin complex, not VBP1 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 VBP1. 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) containing all six subunits including VBP1/PFDN3 to investigate its effect on amyloid-beta aggregation. The successful reconstitution and purification of the hexameric complex provides direct evidence for VBP1 membership in the prefoldin complex. Consistent with IDA from PMID:30955883 and IBA/IEA annotations. Reason: VBP1 is a core structural alpha 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 VBP1 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 VBP1 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:0005737 cytoplasm	TAS PMID:8674032 Identification of a novel protein (VBP-1) binding to the von...	ACCEPT	Summary: GO:0005737 "cytoplasm" (TAS) from Tsuchiya et al. 1996 (PMID:8674032), the original paper that identified VBP1 as a protein binding to the VHL tumor suppressor. This study characterized VBP1 and showed its cytoplasmic localization, with the note that in complex with VHL it can translocate to the nucleus. This is the foundational localization study for VBP1 and is consistent with the IBA and IEA annotations to the same term. Reason: Cytoplasmic localization of VBP1 is well-established from the original discovery paper (PMID:8674032) and is consistent with the known biology of the prefoldin complex operating in the cytoplasm (PMID:9630229). This TAS annotation is appropriate and well-supported.
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 VBP1. Unlike PFDN1, VBP1 lacks an IBA annotation to this term. Gestaut et al. 2019 (PMID:30955883) demonstrated through cryo-EM and biochemical reconstitution that the prefoldin complex (containing VBP1) functions as a co-chaperone that delivers unfolded substrates to TRiC/CCT and enhances the rate and yield of folding. Vainberg et al. 1998 (PMID:9630229) originally characterized prefoldin as "a chaperone that delivers unfolded proteins to cytosolic chaperonin." The GO:0044183 definition ("Binding to a protein or a protein-containing complex to assist the protein folding process") precisely captures the holdase/transfer chaperone function of VBP1 within the prefoldin complex. This is also the recommended replacement for the obsoleting GO:0051082. Reason: GO:0044183 "protein folding chaperone" is the core molecular function of VBP1 as part of the prefoldin complex. This term is missing from the current annotation set (unlike PFDN1 which has it via IBA). The evidence from PMID:30955883 and PMID:9630229 directly supports this annotation. This is also the recommended replacement for GO:0051082 "unfolded protein binding" which is now formally obsolete. 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: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.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

📄 View Raw YAML