PFDN6

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: PFDN6 is a cytoplasmic protein as part of the prefoldin heterohexamer that captures unfolded substrates in the cytoplasm and delivers them to TRiC/CCT. This is well supported by the IBA annotation which is phylogenetically consistent across eukaryotes. UniProt does not specify a subcellular location annotation for PFDN6, but the canonical function of prefoldin as a cytosolic co-chaperone is well established (PMID:9630229). Reason: The cytoplasmic localization is the canonical site of prefoldin function, capturing unfolded actin and tubulin for delivery to TRiC/CCT. The IBA annotation is phylogenetically well supported by data from yeast, plants, worm, and human. 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.
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: Protein folding is the core biological process in which prefoldin participates, capturing non-native substrates and delivering them to TRiC/CCT for productive folding. The IBA annotation is phylogenetically well supported. PFDN6 as a beta subunit contributes directly to this function through its coiled-coil tentacle that engages unfolded substrates (PMID:9630229, PMID:30955883). Reason: Protein folding is the core biological process of the prefoldin complex. The annotation is at the right level of specificity for the BP axis. More specific terms like chaperone-mediated protein complex assembly are also captured separately. Supporting Evidence: PMID:9630229 prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins. PMID:30955883 The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis. file:human/PFDN6/PFDN6-deep-research-falcon.md PFDN6 functions as one beta subunit in the canonical prefoldin hexamer that captures non-native clients, for example nascent actin/tubulin, and delivers them to TRiC/CCT.
GO:0016272 prefoldin complex	IBA GO_REF:0000033	ACCEPT	Summary: PFDN6 is one of the four beta subunits of the canonical prefoldin heterohexamer. This is a core localization for the protein, well established from the original discovery (PMID:9630229) through to recent structural studies (PMID:30955883). The IBA annotation is phylogenetically consistent. Reason: Membership in the prefoldin complex is a defining feature of PFDN6. This is supported by multiple lines of experimental evidence as well as phylogenetic inference. Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. PMID:30955883 these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts
GO:0051087 protein-folding chaperone binding	IBA GO_REF:0000033	ACCEPT	Summary: Prefoldin binds specifically to the TRiC/CCT chaperonin to transfer substrate proteins to it for folding. The interaction between prefoldin and TRiC/CCT is mediated through a conserved electrostatic interface (PMID:30955883). This MF term accurately captures the binding of prefoldin subunits to the downstream chaperonin. Reason: Binding to the TRiC/CCT chaperonin is a core molecular function of prefoldin subunits. The IBA annotation is consistent with experimental data showing prefoldin-TRiC/CCT interaction through a conserved electrostatic interface. Supporting Evidence: PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it. PMID:30955883 these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts that serves as a pivot point for a TRiC-PFD conformational cycle.
GO:0051131 chaperone-mediated protein complex assembly	IBA GO_REF:0000033	ACCEPT	Summary: Prefoldin assists in the assembly of cytoskeletal protein complexes by capturing unfolded actin and tubulin monomers and delivering them to TRiC/CCT, which folds them into conformations competent for polymerization and complex assembly. The IBA annotation is consistent with experimental evidence (PMID:9630229). Reason: This term appropriately captures the role of prefoldin in assisting the chaperonin-mediated assembly of cytoskeletal complexes (actin filaments, tubulin heterodimers/microtubules). The IBA annotation is phylogenetically well supported. 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:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain IPR002777 (PFD_beta-like). This is consistent with the experimentally validated function and the IBA annotation for the same term. While redundant with the IBA and IDA annotations, it is not incorrect. Reason: The IEA mapping from the PFD_beta-like domain to protein folding is appropriate and consistent with the experimentally determined function. Redundancy with other evidence codes is acceptable.
GO:0016272 prefoldin complex	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation from InterPro domain IPR002777 (PFD_beta-like). Consistent with the well-established membership of PFDN6 in the prefoldin complex. Redundant with IBA and IDA annotations but not incorrect. Reason: The IEA mapping from the prefoldin beta domain to prefoldin complex membership is appropriate and consistent with multiple other lines of evidence.
GO:0032991 protein-containing complex	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA machine-learning-derived annotation placing PFDN6 in a protein-containing complex. While technically correct, this is extremely generic and adds no information beyond what is already captured by the more specific GO:0016272 prefoldin complex annotations. Reason: While not technically false, this IEA annotation is too broad to be useful for PFDN6 and is superseded by the more specific GO:0016272 prefoldin complex annotations already present.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: IEA annotation from InterPro domain mapping. While prefoldin does bind unfolded proteins, GO:0051082 "unfolded protein binding" is a molecular function term that describes simple binding to unfolded proteins. The more accurate molecular function for prefoldin is GO:0044183 "protein folding chaperone" which captures the active chaperone role of binding to assist the protein folding process, rather than merely binding unfolded proteins. Reason: Prefoldin does not merely bind unfolded proteins passively; it actively functions as a co-chaperone that captures non-native substrates and delivers them to TRiC/CCT. GO:0044183 "protein folding chaperone" (defined as "Binding to a protein or a protein-containing complex to assist the protein folding process") better describes this active molecular function. Proposed replacements: protein folding chaperone
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput binary interactome mapping study (HuRI). PFDN6 interacts with various proteins including MAGEB4, MBD3, CEBPG, FBXO2, KANK2, KIFC3, RPRD1B, AIMP2, and CCHCR1. While these interactions were detected in a systematic screen, protein binding is uninformative as a GO annotation. Reason: Per curation guidelines, GO:0005515 protein binding is uninformative and should be avoided. The high-throughput interactome data does not provide specific enough functional insight to assign a more informative molecular function term. The known functional interactions (with TRiC/CCT, with other prefoldin subunits) are already captured by more specific annotations.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	REMOVE	Summary: Interactome mapping in context of neurodegenerative disease proteins. PFDN6 interaction with FGFR3 detected. This is a high-throughput study and protein binding is uninformative. Reason: GO:0005515 protein binding is uninformative per curation guidelines. High-throughput interactome mapping does not provide sufficient context for a more specific annotation.
GO:0050821 protein stabilization	NAS PMID:31738558 Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subuni...	KEEP AS NON CORE	Summary: NAS annotation from ComplexPortal referencing the PAQosome study. PMID:31738558 describes ASDURF as a novel prefoldin-like subunit of the PAQosome and shows that PFDN6 is part of the PAQosome prefoldin-like module. The PAQosome is involved in biogenesis of several protein complexes. While protein stabilization is a downstream consequence of chaperone activity, this annotation is reasonable given the role of prefoldin/PAQosome in preventing aggregation and promoting proper folding. Reason: Protein stabilization is a true downstream consequence of the prefoldin/PAQosome chaperone context, but it is not the core molecular activity. The core role is better captured by protein folding chaperone activity and chaperone-mediated protein complex assembly. Supporting Evidence: PMID:31738558 The PAQosome is an 11-subunit chaperone involved in the biogenesis of several human protein complexes.
GO:0006457 protein folding	NAS PMID:32699605 The functions and mechanisms of prefoldin complex and prefol...	ACCEPT	Summary: NAS annotation from ComplexPortal, citing a review on prefoldin functions and mechanisms. Consistent with the core function of prefoldin in protein folding. Redundant with IBA and IDA annotations but not incorrect. Reason: The NAS annotation for protein folding is consistent with all other evidence. The review article cited comprehensively describes prefoldin's role in protein folding.
GO:0006457 protein folding	NAS PMID:34761191 A comprehensive analysis of prefoldins and their implication...	ACCEPT	Summary: NAS annotation from ComplexPortal citing Herranz-Montoya et al. 2021 comprehensive analysis of prefoldins. This review describes the canonical prefoldin function as escorting misfolded or non-native proteins to group II chaperonins for folding. Consistent with the core function. Reason: Consistent with the well-established protein folding function of prefoldin. Supporting Evidence: PMID:34761191 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: NAS annotation from ComplexPortal citing Herranz-Montoya et al. 2021 review. Prefoldin prevents aggregation of non-native proteins, which constitutes protein stabilization. This is a legitimate aspect of the prefoldin function. Reason: Protein stabilization through prevention of aggregation is a documented consequence of prefoldin holdase activity, but it is downstream of the core chaperone mechanism rather than a primary molecular function for PFDN6.
GO:0050821 protein stabilization	NAS PMID:29662061 RPAP3 provides a flexible scaffold for coupling HSP90 to the...	KEEP AS NON CORE	Summary: NAS annotation from ComplexPortal citing PMID:29662061 (Martino et al. 2018) about RPAP3 coupling HSP90 to the R2TP co-chaperone complex. PFDN6 is part of the PAQosome which includes the R2TP complex and prefoldin-like module. The PAQosome stabilizes client complexes during their assembly, so protein stabilization is a reasonable annotation. Reason: Protein stabilization is appropriate as a downstream, non-core annotation for PFDN6 as part of the PAQosome. The core functional interpretation remains prefoldin-like chaperone activity and client complex assembly rather than stabilization as the primary role. Supporting Evidence: PMID:29662061 RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex.
GO:0006457 protein folding	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	ACCEPT	Summary: IDA annotation from Gestaut et al. 2019 (Cell), which used cryo-EM, crosslinking-mass spectrometry and biochemical approaches to characterize the structural and functional interplay between TRiC/CCT and prefoldin. The study showed that PFD can enhance the rate and yield of the TRiC folding reaction and that disrupting the TRiC-PFD interaction leads to accumulation of amyloid aggregates, demonstrating that the supra-chaperone assembly is essential for effective cellular proteostasis. Reason: Strong experimental evidence from a high-quality Cell paper demonstrating that prefoldin cooperates with TRiC/CCT to promote protein folding and prevent toxic conformations. 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. Disrupting the TRiC-PFD interaction in vivo is strongly deleterious, leading to accumulation of amyloid aggregates.
GO:0016272 prefoldin complex	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	ACCEPT	Summary: IDA annotation from Gestaut et al. 2019, which directly visualized the prefoldin-TRiC complex by cryo-EM, confirming the defined architecture of the prefoldin heterohexamer including PFDN6 as a subunit. Reason: Direct experimental demonstration of PFDN6 as part of the prefoldin complex through cryo-EM structural characterization. Supporting Evidence: PMID:30955883 these hetero-oligomeric chaperones associate in a defined architecture, through a conserved interface of electrostatic contacts
GO:0051082 unfolded protein binding	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	MODIFY	Summary: IDA annotation from Gestaut et al. 2019. The study demonstrated that prefoldin captures unfolded substrates and transfers them to TRiC/CCT. However, the molecular function of prefoldin is better described as GO:0044183 "protein folding chaperone" rather than simple unfolded protein binding, because prefoldin actively assists in the folding process by transferring substrates to TRiC/CCT rather than merely binding unfolded proteins. Reason: The prefoldin complex does not merely bind unfolded proteins; it functions as an active co-chaperone that captures non-native substrates and delivers them to TRiC/CCT. GO:0044183 "protein folding chaperone" better captures this molecular function. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:30955883 PFD alternates between an open "latched" conformation and a closed "engaged" conformation that aligns the PFD-TRiC substrate binding chambers. PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction
GO:0001540 amyloid-beta binding	IDA PMID:23614719 Human prefoldin inhibits amyloid-β (Aβ) fibrillation and con...	KEEP AS NON CORE	Summary: IDA annotation from Sorgjerd et al. 2013 (Biochemistry). The study demonstrated that recombinant human prefoldin (hPFD, the full heterohexameric complex) inhibits amyloid-beta (1-42) fibrillation and induces formation of soluble Abeta oligomers that are less toxic (30-40% less toxic than fibrils or archaeal PFD-formed oligomers). This demonstrates that the prefoldin complex as a whole binds amyloid-beta. However, the annotation is made at the level of individual subunits (PFDN6), whereas the binding is a property of the assembled hexamer complex, not of PFDN6 alone. Reason: The amyloid-beta binding was demonstrated for the assembled prefoldin heterohexamer, not for PFDN6 individually. While technically each subunit participates in the complex that binds Abeta, this is not a core function of the gene product and may represent an in vitro property of the holo-complex rather than a physiological role of the individual subunit. Supporting Evidence: PMID:23614719 we investigated the effect of recombinant human PFD (hPFD) on Aβ(1-42) aggregation in vitro and found that hPFD inhibited Aβ fibrillation and induced formation of soluble Aβ oligomers.
GO:0016272 prefoldin complex	IDA PMID:23614719 Human prefoldin inhibits amyloid-β (Aβ) fibrillation and con...	ACCEPT	Summary: IDA annotation from Sorgjerd et al. 2013. The study used recombinant human prefoldin (assembled as a heterohexamer) demonstrating that PFDN6 is part of the complex. Reason: Consistent with all other evidence for PFDN6 membership in the prefoldin complex. 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: IDA annotation from Sorgjerd et al. 2013. The study showed that the full recombinant human prefoldin complex inhibits amyloid-beta fibrillation in vitro, with Abeta oligomers formed in the presence of hPFD being 30-40% less toxic. This is a property of the assembled prefoldin complex, not specific to PFDN6 individually. While interesting, this represents an in vitro observation with the holo-complex rather than a core physiological function of the PFDN6 gene product. Reason: The negative regulation of amyloid fibril formation was demonstrated for the full prefoldin heterohexameric complex in vitro. While potentially relevant to Alzheimer's disease biology, this is not a core evolved function of PFDN6 specifically. The annotation is kept as non-core because the evidence is valid but represents a property of the holo-complex. Supporting Evidence: PMID:23614719 hPFD inhibited Aβ fibrillation and induced formation of soluble Aβ oligomers. Interestingly, cell viability measurements ... showed that Aβ oligomers formed by hPFD were 30-40% less toxic
GO:0016272 prefoldin complex	IDA PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	ACCEPT	Summary: IDA annotation from the seminal Vainberg et al. 1998 (Cell) paper that first described the discovery of prefoldin as a heterohexameric chaperone. PFDN6 was identified as one of the six subunits of this complex. Reason: Foundational experimental evidence from the original discovery of prefoldin. Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin.
GO:0051082 unfolded protein binding	NAS PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	MODIFY	Summary: NAS annotation from the original Vainberg et al. 1998 paper. The paper demonstrated that prefoldin captures unfolded actin and delivers it to the chaperonin. However, the molecular function is better described as GO:0044183 "protein folding chaperone" since prefoldin actively assists in folding rather than merely binding unfolded proteins. Reason: The original paper demonstrates that prefoldin's function goes beyond simple unfolded protein binding; it actively captures and transfers substrates to the chaperonin for productive folding. GO:0044183 "protein folding chaperone" is the more appropriate molecular function term. Proposed replacements: protein folding chaperone Supporting Evidence: 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:0051087 protein-folding chaperone binding	IDA PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	ACCEPT	Summary: IDA annotation from Vainberg et al. 1998. The paper directly demonstrated that prefoldin binds specifically to cytosolic chaperonin (c-CPN/TRiC/CCT) and transfers target proteins to it. This is strong direct experimental evidence for chaperonin binding. Reason: Direct experimental demonstration that prefoldin binds specifically to the cytosolic chaperonin, which is the defining molecular interaction for prefoldin's function. Supporting Evidence: PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
GO:0051131 chaperone-mediated protein complex assembly	IDA PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	ACCEPT	Summary: IDA annotation from Vainberg et al. 1998. The paper showed that deletion of a prefoldin subunit gene in yeast results in impaired functions of the actin and tubulin-based cytoskeleton, demonstrating prefoldin's role in chaperone-mediated assembly of cytoskeletal complexes. Reason: Direct experimental evidence from genetic studies showing that prefoldin is required for proper assembly of cytoskeletal protein complexes. 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:0006457 protein folding	NAS PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	ACCEPT	Summary: NAS annotation from the original Vainberg et al. 1998 paper describing prefoldin's role in protein folding. The paper demonstrated that prefoldin promotes folding by directing target proteins to the chaperonin. Redundant with IDA and IBA annotations but consistent. Reason: Consistent with the well-established protein folding function of prefoldin, supported by the foundational paper. Supporting Evidence: PMID:9630229 we show that by directing target proteins to chaperonin, prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins.
GO:0044183 protein folding chaperone	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	NEW	Summary: PFDN6, as a subunit of the prefoldin complex, functions as a protein folding chaperone that captures non-native substrates and delivers them to TRiC/CCT. This molecular function term is more appropriate than GO:0051082 "unfolded protein binding" because it captures the active co-chaperone role rather than passive binding. Gestaut et al. 2019 demonstrated that prefoldin alternates between conformations to align substrate binding chambers with TRiC/CCT and enhances the rate and yield of the folding reaction (PMID:30955883). Reason: GO:0044183 "protein folding chaperone" is the most appropriate molecular function term for prefoldin subunits. It is defined as "Binding to a protein or a protein-containing complex to assist the protein folding process" which exactly matches prefoldin's function. This annotation should replace the existing GO:0051082 annotations. Supporting Evidence: PMID:30955883 PFD alternates between an open "latched" conformation and a closed "engaged" conformation that aligns the PFD-TRiC substrate binding chambers. 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 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:1990062 RPAP3/R2TP/prefoldin-like complex	IPI PMID:29662061 RPAP3 provides a flexible scaffold for coupling HSP90 to the...	NEW	Summary: PFDN6 is part of the PAQosome/R2TP prefoldin-like module together with PFDN2, URI1, UXT, and PDRG1. This NEW cellular component annotation captures the PAQosome/PFDL complex membership separately from canonical prefoldin complex membership. Reason: GO:1990062 is the specific cellular component term for the RPAP3/R2TP/prefoldin-like complex. UniProt and Martino et al. 2018 both support PFDN6 membership in this PAQosome/PFDL module. Supporting Evidence: file:human/PFDN6/PFDN6-uniprot.txt Component of the PAQosome complex which is responsible for the biogenesis of several protein complexes and which consists of R2TP complex members RUVBL1, RUVBL2, RPAP3 and PIH1D1, URI complex members PFDN2, PFDN6, PDRG1, UXT and URI1 as well as ASDURF, POLR2E and DNAAF10/WDR92. PMID:29662061 This PFDL module includes prefoldin and prefoldin-like proteins PFDN2, PFDN6, URI1, UXT, PDRG1, and it associates with two additional components, the RNA polymerase subunit POLR2E/RPB5 and WDR92/Monad5.

Gene Description

Existing Annotations Review

Core Functions

References

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