Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytoplasm localization. Prefoldin is a cytosolic chaperone complex; PFDN2 functions primarily in the cytoplasm where it captures nascent actin and tubulin and delivers them to TRiC/CCT (PMID:9630229). Experimental evidence from PMID:16876117 and PMID:17936702 confirms cytoplasmic localization by immunofluorescence. Reason: Core localization. The IBA annotation is phylogenetically supported and confirmed by multiple experimental studies showing cytoplasmic localization of PFDN2. Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. PMID:16876117 Prefoldin 2 is a subunit of a hexameric molecular chaperone complex, named prefoldin, which delivers nascent actin and tubulin proteins to the eukaryotic cytosolic chaperonin for facilitated folding.
GO:0006457 protein folding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein folding. Prefoldin is a co-chaperone that participates in protein folding by capturing unfolded substrates and delivering them to TRiC/CCT (PMID:9630229, PMID:30955883). Well-established core function. Reason: Core biological process for prefoldin. The IBA is phylogenetically well-supported and consistent with extensive biochemical evidence for prefoldin's role in protein folding. 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.
GO:0044183 protein folding chaperone	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein folding chaperone molecular function. GO:0044183 is defined as "Binding to a protein or a protein-containing complex to assist the protein folding process." This precisely describes prefoldin's holdase function - binding unfolded substrates and transferring them to TRiC/CCT (PMID:9630229, PMID:30955883). Reason: This is the correct and most appropriate MF term for prefoldin subunits. Prefoldin acts as a holdase/transfer chaperone, binding unfolded actin and tubulin and delivering them to TRiC/CCT. The IBA is well-supported phylogenetically. 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:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for nuclear localization based on UniProt subcellular location mapping. Nuclear localization of PFDN2 is supported by experimental evidence from PMID:17936702 (immunofluorescence) and by functional studies showing prefoldin subunits on transcribed chromatin supporting RNAPII CTD phosphorylation and co-transcriptional splicing. Reason: Although IEA, this is consistent with experimental data from PMID:17936702 and PMID:16876117 showing nuclear localization, plus functional evidence for nuclear roles in transcription/splicing. Supporting Evidence: PMID:17936702 URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: IEA annotation for cytoplasm based on UniProt subcellular location mapping. Redundant with the IBA annotation for the same term but from a different source. Cytoplasmic localization is well-established experimentally. Reason: Duplicates the IBA annotation but from IEA source. Both are valid. Cytoplasmic localization is well-supported.
GO:0005739 mitochondrion	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: IEA annotation for mitochondrial localization. PMID:17936702 identified PFDN2 interaction with URI1 in a mitochondrial context. This was confirmed by IDA evidence in the same dataset. Mitochondrial localization relates to the URI/PAQosome complex rather than canonical prefoldin function. Reason: Mitochondrial localization is experimentally supported (PMID:17936702) but relates to the URI1/PAQosome interaction rather than canonical prefoldin chaperone function. Not a core localization for prefoldin function. Supporting Evidence: PMID:17936702 URI represents a mitochondrial substrate of S6K1
GO:0006457 protein folding	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for protein folding based on InterPro domain mapping. Consistent with the IBA and IDA annotations for the same term. Prefoldin's role in protein folding is well-established. Reason: Redundant with IBA and IDA annotations for the same term. The InterPro-based mapping is correct and consistent with the known function of prefoldin.
GO:0016272 prefoldin complex	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for prefoldin complex based on InterPro domain mapping. PFDN2 is a well-established component of the canonical prefoldin heterohexameric complex, confirmed by cryo-EM structures (PDB:6NR8, 7WU7) and biochemical studies (PMID:9630229, PMID:30955883). Reason: Core cellular component. PFDN2 is a structural subunit of the prefoldin complex, confirmed by multiple structures and biochemical characterization. Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin
GO:0032991 protein-containing complex	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: IEA annotation from ARBA machine learning for generic protein-containing complex. This is technically correct but too general - PFDN2 is specifically part of the prefoldin complex (GO:0016272) which is already annotated. Reason: Too generic. The more specific term GO:0016272 (prefoldin complex) is already annotated and better describes the actual complex membership. This parent term adds no information.
GO:0051082 unfolded protein binding	IEA GO_REF:0000002	MODIFY	Summary: IEA annotation for unfolded protein binding based on InterPro mapping. While prefoldin does bind unfolded proteins, the more informative and accurate MF term is GO:0044183 (protein folding chaperone), which captures the functional role of binding unfolded substrates to assist folding, not merely binding them. Reason: GO:0051082 "unfolded protein binding" describes only the binding aspect. The correct MF term for prefoldin is GO:0044183 "protein folding chaperone" which captures the complete holdase/transfer chaperone function. The IBA already uses GO:0044183. Proposed replacements: protein folding chaperone
GO:0005515 protein binding	IPI PMID:15923622 The HRPT2 tumor suppressor gene product parafibromin associa...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from PMID:15923622 (Yart et al., 2005). This paper is about parafibromin (HRPT2) associating with PAF1 and RNAPII. The interaction with PFDN2 may have been detected as part of a larger interactome study. The generic protein binding term is uninformative. Reason: Generic protein binding from a study focused on parafibromin/PAF1/RNAPII. Does not provide specific functional information about PFDN2. The term "protein binding" is uninformative per curation guidelines.
GO:0005515 protein binding	IPI PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from PMID:16876117 (Tsao et al., 2006). This study demonstrated that HCV F protein interacts with PFDN2 via yeast two-hybrid and co-immunoprecipitation. The interaction impedes PFDN1-PFDN2 interaction and perturbs tubulin cytoskeleton. While a genuine interaction, the generic term is uninformative. Reason: Generic protein binding. The actual functional annotation from this paper (protein folding chaperone activity, positive regulation of cytoskeleton organization) is captured by other annotations from the same reference. Supporting Evidence: PMID:16876117 hepatitis C virus (HCV) F protein was found to interact with a cellular protein named prefoldin 2
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from large-scale mass spectrometry interactome study (Ewing et al., 2007). High-throughput interactome data. Generic protein binding is uninformative. Reason: Generic protein binding from high-throughput interactome study. Uninformative per curation guidelines.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from quantitative chaperone interaction network study (Taipale et al., 2014). While this study provides valuable context about PFDN2's position in the chaperone network, the generic protein binding term is uninformative. Reason: Generic protein binding from chaperone interactome study. The actual functional annotations from prefoldin studies are better captured by GO:0044183.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from large-scale interactome architecture study (Huttlin et al., 2017). High-throughput study. Generic term is uninformative. Reason: Generic protein binding from high-throughput interactome study. Uninformative.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: IPI protein binding from binary protein interactome reference map (Luck et al., 2020). High-throughput study. Generic term is uninformative. Reason: Generic protein binding from high-throughput interactome study. Uninformative.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from neurodegenerative disease protein interactome mapping study (Haenig et al., 2020). High-throughput study. Generic term is uninformative. Reason: Generic protein binding from high-throughput interactome study. Uninformative.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from dual proteome-scale network study. High-throughput study. Generic term is uninformative. Reason: Generic protein binding from high-throughput interactome study. Uninformative.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from multimodal cell maps study. High-throughput study. Generic term is uninformative. Reason: Generic protein binding from high-throughput interactome study. Uninformative.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation for nucleoplasm based on immunofluorescence data curation (HPA). Consistent with known nuclear roles of prefoldin subunits in transcription elongation and co-transcriptional splicing. Reason: Supported by immunofluorescence data from HPA and consistent with nuclear functions of prefoldin in transcription/splicing regulation.
GO:0005739 mitochondrion	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: IDA annotation for mitochondrion based on immunofluorescence data curation (HPA). Consistent with PMID:17936702 showing PFDN2 association with URI1 at mitochondria. Reason: Mitochondrial localization is experimentally supported but is a non-core localization relating to URI/PAQosome function rather than canonical prefoldin chaperone activity.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: IDA annotation for cytosol based on immunofluorescence data curation (HPA). Cytosol is the primary site of prefoldin's canonical co-chaperone function. Reason: Core localization. Cytosol is where prefoldin performs its primary function of capturing nascent actin/tubulin and delivering to TRiC/CCT.
GO:0050821 protein stabilization	NAS PMID:31738558 Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subuni...	KEEP AS NON CORE	Summary: NAS annotation for protein stabilization from PMID:31738558 (Cloutier et al., 2020). This paper describes ASDURF as a novel prefoldin-like subunit of the PAQosome, which includes PFDN2. The PAQosome is involved in biogenesis of protein complexes, which involves stabilization. Prefoldin's holdase activity does stabilize unfolded proteins against aggregation. Reason: Protein stabilization is a secondary consequence of prefoldin's holdase function. The primary function is better captured as protein folding chaperone. Stabilization is not incorrect but is a secondary effect rather than core function.
GO:0006457 protein folding	NAS PMID:32699605 The functions and mechanisms of prefoldin complex and prefol...	ACCEPT	Summary: NAS annotation for protein folding from the review by Liang et al. (2020) covering prefoldin functions and mechanisms. Consistent with core function. Reason: Redundant with IBA and IDA annotations but from a review source. Protein folding is a core function of prefoldin.
GO:0006457 protein folding	NAS PMID:34761191 A comprehensive analysis of prefoldins and their implication...	ACCEPT	Summary: NAS annotation for protein folding from Herranz-Montoya et al. (2021) comprehensive analysis of prefoldins. Consistent with core function. Reason: Redundant with other protein folding annotations. Consistent with the well-established core function of the prefoldin complex.
GO:0050821 protein stabilization	NAS PMID:34761191 A comprehensive analysis of prefoldins and their implication...	KEEP AS NON CORE	Summary: NAS annotation for protein stabilization from Herranz-Montoya et al. (2021). Prefoldin stabilizes client proteins (e.g., VHL) against aggregation. Reason: Protein stabilization is a secondary consequence of prefoldin's holdase function, not the primary molecular activity. Core function is better captured as protein folding chaperone.
GO:0050821 protein stabilization	NAS PMID:29662061 RPAP3 provides a flexible scaffold for coupling HSP90 to the...	KEEP AS NON CORE	Summary: NAS annotation for protein stabilization from PMID:29662061 (Martino et al., 2018). This paper is about RPAP3 providing a scaffold for coupling HSP90 to the R2TP co-chaperone complex. Relevant to the PAQosome context of PFDN2. Reason: Relates to the R2TP/PAQosome complex stabilization function. Not a core function of PFDN2 in the canonical prefoldin complex.
GO:0006457 protein folding	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	ACCEPT	Summary: IDA annotation for protein folding from Gestaut et al. (2019) Cell paper. This landmark study used cryo-EM, crosslinking-MS, and biochemical approaches to show that prefoldin associates with TRiC/CCT through a conserved electrostatic interface, with PFD enhancing folding rate and yield while suppressing non-productive cycles. Reason: Strong experimental evidence from a landmark Cell paper demonstrating the structural and functional basis for prefoldin-TRiC cooperation in protein folding. 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.
GO:0016272 prefoldin complex	IDA PMID:30955883 The Chaperonin TRiC/CCT Associates with Prefoldin through a ...	ACCEPT	Summary: IDA annotation for prefoldin complex from Gestaut et al. (2019). Cryo-EM structures of the prefoldin-TRiC complex were resolved, directly demonstrating prefoldin complex architecture. Reason: Strong structural evidence from cryo-EM demonstrating prefoldin complex structure in association with TRiC/CCT. Supporting Evidence: PMID:30955883 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: IDA annotation for unfolded protein binding from Gestaut et al. (2019). While prefoldin does bind unfolded proteins, the more accurate MF term is GO:0044183 (protein folding chaperone) which captures the complete functional role. Reason: GO:0051082 describes only the binding aspect. GO:0044183 "protein folding chaperone" better captures prefoldin's complete holdase/transfer function. The binding is in service of assisted folding, not binding per se. 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.
GO:0001540 amyloid-beta binding	IDA PMID:23614719 Human prefoldin inhibits amyloid-β (Aβ) fibrillation and con...	KEEP AS NON CORE	Summary: IDA annotation for amyloid-beta binding from Sorgjerd et al. (2013). The study demonstrated that recombinant human prefoldin (hPFD) inhibits Abeta fibrillation and induces formation of less toxic Abeta oligomers. This is a property of the intact hexameric complex, not specific to PFDN2. Reason: The study demonstrated Abeta binding as a property of the intact prefoldin complex. This is consistent with prefoldin's general holdase function against misfolded proteins. However, this is not a core physiological function but rather reflects the general anti-aggregation capacity of the complex. 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: IDA annotation for prefoldin complex from Sorgjerd et al. (2013). The study used recombinant human prefoldin complex to study Abeta interactions, confirming the hexameric complex assembly. Reason: Confirms prefoldin complex formation with recombinant human subunits.
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 for negative regulation of amyloid fibril formation from Sorgjerd et al. (2013). The study showed hPFD inhibits Abeta fibrillation in vitro. This is a property of the intact complex and reflects the general anti-aggregation holdase function. Reason: This reflects in vitro anti-aggregation activity of the prefoldin complex rather than a primary physiological function. It is a secondary consequence of the holdase activity. The annotation is not wrong but represents a non-core function. Supporting Evidence: PMID:23614719 hPFD inhibited Abeta fibrillation and induced formation of soluble Abeta oligomers. Interestingly, cell viability measurements...showed that Abeta oligomers formed by hPFD were 30-40% less toxic
GO:0005634 nucleus	IDA PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	ACCEPT	Summary: IDA annotation for nuclear localization from Tsao et al. (2006). The study used confocal immunofluorescence microscopy and showed PFDN2 in both nucleus and cytoplasm. Reason: Experimental evidence (immunofluorescence) supports nuclear localization. Consistent with known nuclear roles of prefoldin in transcription and splicing regulation. Supporting Evidence: PMID:16876117 The interaction was confirmed by confocal immunofluorescence microscopy as well as coimmunoprecipitation experiments.
GO:0005737 cytoplasm	IDA PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	ACCEPT	Summary: IDA annotation for cytoplasm from Tsao et al. (2006). Immunofluorescence confirms cytoplasmic localization. Reason: Core localization confirmed by experimental immunofluorescence data. Consistent with canonical cytosolic chaperone function.
GO:0044183 protein folding chaperone	IPI PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	ACCEPT	Summary: IPI annotation for protein folding chaperone from Tsao et al. (2006). The study showed PFDN2 interacts with HCV F protein, and that this interaction impedes PFDN1-PFDN2 interaction and perturbs tubulin cytoskeleton. This demonstrates PFDN2's role as a chaperone for tubulin folding. Reason: Demonstrates PFDN2's chaperone function via perturbation - HCV F protein interaction with PFDN2 disrupts prefoldin complex assembly and impairs tubulin folding, confirming PFDN2's role as a protein folding chaperone. Supporting Evidence: PMID:16876117 expression of HCV F protein impeded the interaction between prefoldin 1 and 2...expression of HCV F protein resulted in aberrant organization of tubulin cytoskeleton.
GO:0051495 positive regulation of cytoskeleton organization	IDA PMID:16876117 Interaction of hepatitis C virus F protein with prefoldin 2 ...	KEEP AS NON CORE	Summary: IDA annotation for positive regulation of cytoskeleton organization from Tsao et al. (2006). The study showed that disruption of PFDN2 function (by HCV F protein) leads to aberrant tubulin cytoskeleton organization, implying PFDN2 normally promotes proper cytoskeleton organization through its chaperone activity. Reason: While the study demonstrates that PFDN2 is required for proper cytoskeleton organization, this is a downstream consequence of its chaperone function (folding actin and tubulin) rather than a direct regulatory role. The annotation captures a true biological effect but the mechanism is indirect through protein folding. Supporting Evidence: PMID:16876117 expression of HCV F protein resulted in aberrant organization of tubulin cytoskeleton
GO:0005515 protein binding	IPI PMID:17936702 S6K1-mediated disassembly of mitochondrial URI/PP1gamma comp...	MARK AS OVER ANNOTATED	Summary: IPI protein binding from Djouder et al. (2007). This study showed PFDN2 interaction with URI1 in a phosphorylation-dependent manner. Generic protein binding is uninformative. Reason: Generic protein binding. The interaction with URI1 is more specifically captured by the PAQosome/prefoldin complex annotations.
GO:0005634 nucleus	IDA PMID:17936702 S6K1-mediated disassembly of mitochondrial URI/PP1gamma comp...	ACCEPT	Summary: IDA annotation for nuclear localization from Djouder et al. (2007). The study showed PFDN2 localizes to nucleus, cytoplasm, and mitochondria through immunofluorescence. Reason: Experimental evidence for nuclear localization by immunofluorescence.
GO:0005737 cytoplasm	IDA PMID:17936702 S6K1-mediated disassembly of mitochondrial URI/PP1gamma comp...	ACCEPT	Summary: IDA annotation for cytoplasm from Djouder et al. (2007). Confirmed by immunofluorescence. Reason: Core localization confirmed experimentally.
GO:0005739 mitochondrion	IDA PMID:17936702 S6K1-mediated disassembly of mitochondrial URI/PP1gamma comp...	KEEP AS NON CORE	Summary: IDA annotation for mitochondrial localization from Djouder et al. (2007). PFDN2 interacts with URI1 at mitochondria in a phosphorylation-dependent manner. Reason: Experimentally supported mitochondrial localization, but this relates to the URI1/PAQosome interaction rather than canonical prefoldin chaperone function. Supporting Evidence: PMID:17936702 URI represents a mitochondrial substrate of S6K1
GO:0051082 unfolded protein binding	NAS PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	MODIFY	Summary: NAS annotation for unfolded protein binding from Vainberg et al. (1998), the original prefoldin discovery paper. While accurate that prefoldin binds unfolded proteins, GO:0044183 is the more appropriate MF term. Reason: GO:0051082 describes only the binding aspect. GO:0044183 "protein folding chaperone" better captures the complete holdase/transfer function described in this paper. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:9630229 Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
GO:0016272 prefoldin complex	NAS PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	ACCEPT	Summary: NAS annotation for prefoldin complex from the original prefoldin discovery paper (Vainberg et al., 1998). Describes the heterohexameric complex architecture. Reason: The foundational paper establishing the prefoldin complex. Core annotation. Supporting Evidence: PMID:9630229 We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin.
GO:0006457 protein folding	NAS PMID:9630229 Prefoldin, a chaperone that delivers unfolded proteins to cy...	ACCEPT	Summary: NAS annotation for protein folding from Vainberg et al. (1998). This paper established that prefoldin promotes protein folding by delivering substrates to c-CPN (TRiC/CCT). Reason: Core function established in the original prefoldin paper. Supporting Evidence: PMID:9630229 prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins.

Core Functions

PFDN2 is a beta-type subunit of the heterohexameric prefoldin co-chaperone complex that captures unfolded nascent polypeptides (primarily actin and tubulin) and delivers them to the TRiC/CCT chaperonin for ATP-dependent folding. Disruption of PFDN1-PFDN2 interaction (e.g., by HCV F protein) leads to aberrant tubulin cytoskeleton organization, confirming the functional importance of PFDN2 in cytoskeletal protein folding.

Molecular Function:

protein folding chaperone

Directly Involved In:

protein folding

Cellular Locations:

cytosol

In Complex:

prefoldin complex

Supporting Evidence:

PMID:9630229
We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin. Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
PMID:30955883
PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles.
PMID:16876117
expression of HCV F protein impeded the interaction between prefoldin 1 and 2...expression of HCV F protein resulted in aberrant organization of tubulin cytoskeleton.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:15923622

The HRPT2 tumor suppressor gene product parafibromin associates with human PAF1 and RNA polymerase II.

PMID:16876117

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

PFDN2 interacts with HCV F protein via yeast two-hybrid and co-IP
HCV F protein impedes PFDN1-PFDN2 interaction
Disruption leads to aberrant tubulin cytoskeleton organization

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:17936702

S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling.

PFDN2 interacts with URI1 in phosphorylation-dependent manner
PFDN2 localizes to nucleus, cytoplasm, and mitochondria

PMID:23614719

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

Recombinant human prefoldin inhibits Abeta fibrillation
hPFD induces formation of less toxic Abeta oligomers

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:28514442

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

PMID:29662061

RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone complex.

PMID:30955883

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

Cryo-EM structure of prefoldin-TRiC complex
Conserved electrostatic interface between PFD and TRiC
PFD enhances folding rate and yield

PMID:31738558

Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subunit of the PAQosome.

PFDN2 is a component of the PAQosome complex
PAQosome contains prefoldin-like module with PFDN2 and PFDN6

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32699605

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

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33961781

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

PMID:34761191

A comprehensive analysis of prefoldins and their implication in cancer.

PMID:40205054

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

PMID:9630229

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

Discovery of prefoldin as heterohexameric chaperone
Prefoldin captures unfolded actin and delivers to cytosolic chaperonin
Promotes folding in competitive environment

📚 Additional Documentation

Deep Research Falcon

(PFDN2-deep-research-falcon.md)

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gene_id: PFDN2
gene_symbol: PFDN2
uniprot_accession: Q9UHV9
protein_description: 'RecName: Full=Prefoldin subunit 2;'
gene_info: Name=PFDN2; Synonyms=PFD2; ORFNames=HSPC231;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the prefoldin subunit beta family.
protein_domains: PFD2. (IPR027235); PFD_beta-like. (IPR002777); Prefoldin. (IPR009053);
Prefoldin_2 (PF01920)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

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

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9UHV9
Protein Description: RecName: Full=Prefoldin subunit 2;
Gene Information: Name=PFDN2; Synonyms=PFD2; ORFNames=HSPC231;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the prefoldin subunit beta family.
Key Domains: PFD2. (IPR027235); PFD_beta-like. (IPR002777); Prefoldin. (IPR009053); Prefoldin_2 (PF01920)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PFDN2" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

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

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'PFDN2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene PFDN2 (gene ID: PFDN2, UniProt: Q9UHV9) in human.

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

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

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

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

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

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

Output

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

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

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

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

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

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q9UHV9
Protein Description: RecName: Full=Prefoldin subunit 2;
Gene Information: Name=PFDN2; Synonyms=PFD2; ORFNames=HSPC231;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the prefoldin subunit beta family.
Key Domains: PFD2. (IPR027235); PFD_beta-like. (IPR002777); Prefoldin. (IPR009053); Prefoldin_2 (PF01920)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "PFDN2" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

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

Research Target:

Please provide a comprehensive research report on the gene PFDN2 (gene ID: PFDN2, UniProt: Q9UHV9) in human.

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

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

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

Research plan and verification
We first verified the target identity to avoid gene symbol ambiguity. Human PFDN2 (UniProt Q9UHV9) encodes prefoldin subunit 2, a beta-class subunit of the canonical heterohexameric prefoldin complex (alpha subunits PFDN3/PFDN5; beta subunits PFDN1/PFDN2/PFDN4/PFDN6) in Homo sapiens, consistent with membership in the prefoldin beta family and associated domains noted for this subunit (IPR002777, IPR009053) (herranzmontoya2021acomprehensiveanalysis pages 1-2, tahmaz2022prefoldinfunctionin pages 1-2, chesnel2020theprefoldincomplex pages 1-2).

Comprehensive research report on PFDN2 (Homo sapiens)
1) Key concepts and definitions with current understanding
- Molecular identity and complex architecture: Prefoldin (PFDN) is an evolutionarily conserved heterohexameric co-chaperone that functions as an ATP-independent holdase. Eukaryotic canonical prefoldin is built from two alpha and four beta subunits; PFDN2 is one of the four beta subunits in the human canonical complex (and is also represented in prefoldin-like assemblies) (iScience, Nov 2021; https://doi.org/10.1016/j.isci.2021.103273) (herranzmontoya2021acomprehensiveanalysis pages 1-2). Reviews corroborate the composition (alpha: PFD3, PFD5; beta: PFD1, PFD2, PFD4, PFD6) and jellyfish-like architecture that captures non-native polypeptides via coiled tentacles (Frontiers in Cell and Developmental Biology, Jan 2022; https://doi.org/10.3389/fcell.2021.816214) (tahmaz2022prefoldinfunctionin pages 1-2) and (PLOS Genetics, Nov 2020; https://doi.org/10.1371/journal.pgen.1009183) (chesnel2020theprefoldincomplex pages 1-2).
- Canonical function—client delivery to TRiC/CCT: In eukaryotes, the canonical role of prefoldin is to bind nascent, non-native actin and tubulin chains co-translationally and deliver them to the group II chaperonin TRiC/CCT for ATP-dependent folding. This division of labor is well established biochemically and structurally, and depletion of prefoldin subunits perturbs cytoskeletal assembly in human cells (iScience, 2021; https://doi.org/10.1016/j.isci.2021.103273; Frontiers in Cell and Developmental Biology, 2022; https://doi.org/10.3389/fcell.2021.816214) (herranzmontoya2021acomprehensiveanalysis pages 5-7, tahmaz2022prefoldinfunctionin pages 2-3, herranzmontoya2021acomprehensiveanalysis pages 1-2, tahmaz2022prefoldinfunctionin pages 1-2).
- Non-canonical functions: Beyond cytosolic proteostasis, prefoldin subunits (including PFDN2) localize to the nucleus and contribute to transcriptional regulation and co-transcriptional RNA processing. Prefoldin associates with transcribed chromatin and supports efficient elongation-linked splicing by sustaining RNA polymerase II (RNAPII) CTD phosphorylation states and recruiting splicing factors (Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (payanbravo2021humanprefoldinmodulates pages 1-4).

2) Recent developments and latest research (prioritize 2023–2024)
- Ultra-deep proteomic mapping of human prefoldin assemblies (2024): Using DIP-MS, a single-experiment, deep interactome profiling approach, a comprehensive map of human prefoldin family complexes centered on PFDN2 was generated. The study resolved holo- and subcomplex variants, identified alternative assemblies (including a prefoldin homolog complex), and quantified coelution/co-association with TRiC/CCT and known substrates such as tubulin (TUBB2B). Replicate-resolved interaction probabilities and structural modeling aligned predicted assemblies to experimental prefoldin structures (Nature Methods, Mar 2024; https://doi.org/10.1038/s41592-024-02211-y) (fabian2024dipmsultradeepinteraction pages 7-8).
- Canonical and nuclear roles consolidated: Contemporary reviews and functional studies continue to support prefoldin’s dual life in cytosol and nucleus, with evidence that prefoldin’s impact extends to transcription elongation-coupled splicing and global gene expression programs in human cells, including direct perturbation with PFDN2 siRNA (Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (payanbravo2021humanprefoldinmodulates pages 1-4) and updated syntheses of canonical cytoskeletal client handling (Frontiers in Cell and Developmental Biology, 2022; https://doi.org/10.3389/fcell.2021.816214) (tahmaz2022prefoldinfunctionin pages 2-3, tahmaz2022prefoldinfunctionin pages 1-2).

3) Current applications and real-world implementations
- Proteostasis and cytoskeletal integrity: Prefoldin’s support of actin/tubulin folding is fundamental to cell division and motility. Experimental perturbation of prefoldin subunits (including the beta subfamily to which PFDN2 belongs) leads to microtubule abnormalities and aggregation-prone states for certain client proteins, highlighting potential leverage points for cell biology tools and disease modeling (iScience, 2021; https://doi.org/10.1016/j.isci.2021.103273; PLOS Genetics, 2020; https://doi.org/10.1371/journal.pgen.1009183) (herranzmontoya2021acomprehensiveanalysis pages 5-7, chesnel2020theprefoldincomplex pages 1-2).
- Complex-centric proteomics: DIP-MS can be used to deconvolute prefoldin isoforms and interaction partners in a single experiment, enabling systems-level dissection of prefoldin function or dysfunction in disease models and drug perturbations (Nature Methods, Mar 2024; https://doi.org/10.1038/s41592-024-02211-y) (fabian2024dipmsultradeepinteraction pages 7-8).
- Nuclear gene regulation: The demonstration that prefoldin supports RNAPII CTD Ser2/Ser5 phosphorylation and co-transcriptional splicing suggests applications where PFDN2 perturbation serves as a tool to modulate elongation rate and splicing efficiency in mammalian gene expression studies (Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (payanbravo2021humanprefoldinmodulates pages 1-4).

4) Expert opinions and analysis from authoritative sources
- Mechanistic consensus: Authoritative reviews converge on the model that canonical prefoldin binds nascent cytoskeletal clients and hands them to TRiC/CCT, acting as an ATP-independent holdase that increases the efficiency of cytoskeletal protein maturation. Eukaryotic prefoldin shows specialized recognition properties compared with archaeal homologs, reflecting adaptation to actin/tubulin clients (iScience, 2021; https://doi.org/10.1016/j.isci.2021.103273; Frontiers in Cell and Developmental Biology, 2022; https://doi.org/10.3389/fcell.2021.816214) (herranzmontoya2021acomprehensiveanalysis pages 5-7, tahmaz2022prefoldinfunctionin pages 2-3, herranzmontoya2021acomprehensiveanalysis pages 1-2, tahmaz2022prefoldinfunctionin pages 1-2).
- Nuclear roles are substantive: Functional genomics in human cells indicates prefoldin subunits (including PFDN2) are integral to transcription elongation and co-transcriptional splicing by maintaining RNAPII CTD phosphorylation and recruiting splicing factors to chromatin, extending the prefoldin paradigm into gene regulation (Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (payanbravo2021humanprefoldinmodulates pages 1-4).
- Client spectrum beyond cytoskeleton: Prefoldin can stabilize tumor suppressor VHL against aggregation and degradation, expanding the functional client pool and pathophysiological relevance (PLOS Genetics, Nov 2020; https://doi.org/10.1371/journal.pgen.1009183) (chesnel2020theprefoldincomplex pages 1-2).

5) Relevant statistics and data from recent studies
- Complex architecture and interactions (2024): DIP-MS quantified interaction probabilities across the prefoldin family, resolving distinct prefoldin isoforms, with coelution-based association to TRiC/CCT and known clients, validated in n=3 biologically independent experiments. Structural modeling of alternative assemblies yielded TM-scores consistent with similarity to experimentally determined prefoldin structures, supporting the existence of variant complexes incorporating PFDN2 (Nature Methods, Mar 2024; https://doi.org/10.1038/s41592-024-02211-y) (fabian2024dipmsultradeepinteraction pages 7-8).
- Functional impact on gene expression: siRNA depletion targeting PFDN2 or PFDN5 in HCT116 cells produced genome-wide transcriptional changes with “severe pre-mRNA splicing defects,” most evident after serum stimulation; mechanistically, loss of prefoldin decreased RNAPII CTD Ser2/Ser5 phosphorylation and reduced chromatin association of U2AF65 and PRP19, impairing co-transcriptional splicing of long, intron-rich genes (Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (payanbravo2021humanprefoldinmodulates pages 1-4).
- Efficiency of cytoskeletal folding: Expert synthesis estimates that prefoldin activity enhances cytoskeletal folding efficiency (e.g., actin/tubulin) several-fold compared with spontaneous folding, consistent with prefoldin’s role as a holdase that routes clients to TRiC/CCT; depletion causes microtubule assembly defects (iScience, Nov 2021; https://doi.org/10.1016/j.isci.2021.103273) (herranzmontoya2021acomprehensiveanalysis pages 5-7).

Function, pathways, and localization of PFDN2
- Primary function: PFDN2 is a structural subunit of the canonical eukaryotic prefoldin holdase. It contributes to the capture of nascent or non-native polypeptides—principally cytoskeletal actins and tubulins—and their targeted delivery to TRiC/CCT, which completes ATP-dependent folding. This positions PFDN2 upstream in the cytosolic chaperone network governing cytoskeletal proteostasis (iScience, 2021; https://doi.org/10.1016/j.isci.2021.103273; Frontiers in Cell and Developmental Biology, 2022; https://doi.org/10.3389/fcell.2021.816214) (herranzmontoya2021acomprehensiveanalysis pages 5-7, tahmaz2022prefoldinfunctionin pages 2-3, herranzmontoya2021acomprehensiveanalysis pages 1-2, tahmaz2022prefoldinfunctionin pages 1-2).
- Interacting partners and clients: Partners include TRiC/CCT subunits and cytoskeletal clients (actin/tubulin); modern proteomic mapping detects co-association of PFDN2-containing complexes with TRiC/CCT and tubulin subunits. Prefoldin can also act on additional clients such as VHL, stabilizing it against aggregation (Nature Methods, Mar 2024; https://doi.org/10.1038/s41592-024-02211-y; PLOS Genetics, Nov 2020; https://doi.org/10.1371/journal.pgen.1009183) (fabian2024dipmsultradeepinteraction pages 7-8, chesnel2020theprefoldincomplex pages 1-2).
- Subcellular localization: Prefoldin functions in the cytosol in co-translational capture and transfer of nascent chains. In addition, prefoldin subunits, including PFDN2, are detected on transcribed chromatin in the nucleus, where they support transcription elongation and co-transcriptional splicing via effects on RNAPII CTD phosphorylation and splicing factor recruitment (Frontiers in Cell and Developmental Biology, 2022; https://doi.org/10.3389/fcell.2021.816214; Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (tahmaz2022prefoldinfunctionin pages 2-3, tahmaz2022prefoldinfunctionin pages 1-2, payanbravo2021humanprefoldinmodulates pages 1-4).
- Pathways: PFDN2 participates in the proteostasis pathway that couples ribosome-associated nascent chain capture (holdase) to group II chaperonin-mediated folding (TRiC/CCT). In the nucleus, PFDN2 contributes to transcription elongation-coupled splicing by maintaining RNAPII CTD phosphorylation states and enabling recruitment of U2AF65/PRP19, impacting gene expression programs, especially for long, intron-rich genes (Nucleic Acids Research, Jun 2021; https://doi.org/10.1101/2020.06.14.150466) (payanbravo2021humanprefoldinmodulates pages 1-4).

Disease relevance and translational notes
- Cancer biology links: Prefoldin family members are implicated in tumorigenesis through effects on cytoskeletal dynamics and client maturation; downregulation or dysfunction leads to cytoskeletal defects, and prefoldin interacts with the tumor suppressor VHL, stabilizing it against aggregation. While PFDN2-specific prognostic statistics vary across studies and tumor types, the established client spectrum (cytoskeleton, VHL) and nuclear gene-regulatory functions position PFDN2 as a potential contributor to cancer phenotypes when dysregulated (iScience, Nov 2021; https://doi.org/10.1016/j.isci.2021.103273; PLOS Genetics, Nov 2020; https://doi.org/10.1371/journal.pgen.1009183) (herranzmontoya2021acomprehensiveanalysis pages 5-7, chesnel2020theprefoldincomplex pages 1-2).
- Systems proteomics utility: DIP-MS provides quantifiable interaction maps that can help track prefoldin (and PFDN2) complex remodeling in disease models or under therapeutic perturbations, potentially informing biomarker or target discovery (Nature Methods, Mar 2024; https://doi.org/10.1038/s41592-024-02211-y) (fabian2024dipmsultradeepinteraction pages 7-8).

Citations (URLs and dates)
- Frommelt F et al. DIP-MS: ultra-deep interaction proteomics for the deconvolution of protein complexes. Nature Methods. Mar 2024. https://doi.org/10.1038/s41592-024-02211-y (fabian2024dipmsultradeepinteraction pages 7-8)
- Herranz-Montoya I, Park S, Djouder N. A comprehensive analysis of prefoldins and their implication in cancer. iScience. Nov 2021. https://doi.org/10.1016/j.isci.2021.103273 (herranzmontoya2021acomprehensiveanalysis pages 5-7, herranzmontoya2021acomprehensiveanalysis pages 1-2)
- Tahmaz I, Shahmoradi Ghahe S, Topf U. Prefoldin function in cellular protein homeostasis and human diseases. Frontiers in Cell and Developmental Biology. Jan 2022. https://doi.org/10.3389/fcell.2021.816214 (tahmaz2022prefoldinfunctionin pages 2-3, tahmaz2022prefoldinfunctionin pages 1-2)
- Payán-Bravo L et al. Human prefoldin modulates co-transcriptional pre-mRNA splicing. Nucleic Acids Research. Jun 2021. https://doi.org/10.1101/2020.06.14.150466 (payanbravo2021humanprefoldinmodulates pages 1-4)
- Chesnel F et al. The prefoldin complex stabilizes the von Hippel–Lindau protein against aggregation and degradation. PLOS Genetics. Nov 2020. https://doi.org/10.1371/journal.pgen.1009183 (chesnel2020theprefoldincomplex pages 1-2)

Limitations and open questions
- Although broad roles of prefoldin and its nuclear functions are supported, PFDN2-specific disease associations and quantitative clinical statistics remain less comprehensive in recent primary literature within the retrieved corpus. Further targeted analyses of tumor cohorts and perturbation studies focusing specifically on PFDN2 would refine prognostic and mechanistic inferences (herranzmontoya2021acomprehensiveanalysis pages 5-7, payanbravo2021humanprefoldinmodulates pages 1-4).

References

(herranzmontoya2021acomprehensiveanalysis pages 1-2): Irene Herranz-Montoya, Solip Park, and Nabil Djouder. A comprehensive analysis of prefoldins and their implication in cancer. iScience, 24:103273, Nov 2021. URL: https://doi.org/10.1016/j.isci.2021.103273, doi:10.1016/j.isci.2021.103273. This article has 24 citations and is from a peer-reviewed journal.
(tahmaz2022prefoldinfunctionin pages 1-2): Ismail Tahmaz, Somayeh Shahmoradi Ghahe, and Ulrike Topf. Prefoldin function in cellular protein homeostasis and human diseases. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.816214, doi:10.3389/fcell.2021.816214. This article has 48 citations and is from a poor quality or predatory journal.
(chesnel2020theprefoldincomplex pages 1-2): Franck Chesnel, Anne Couturier, Adrien Alusse, Jean-Philippe Gagné, Guy G. Poirier, Dominique Jean, François-Michel Boisvert, Pauline Hascoet, Luc Paillard, Yannick Arlot-Bonnemains, and Xavier Le Goff. The prefoldin complex stabilizes the von hippel-lindau protein against aggregation and degradation. PLOS Genetics, 16:e1009183, Nov 2020. URL: https://doi.org/10.1371/journal.pgen.1009183, doi:10.1371/journal.pgen.1009183. This article has 16 citations and is from a domain leading peer-reviewed journal.
(herranzmontoya2021acomprehensiveanalysis pages 5-7): Irene Herranz-Montoya, Solip Park, and Nabil Djouder. A comprehensive analysis of prefoldins and their implication in cancer. iScience, 24:103273, Nov 2021. URL: https://doi.org/10.1016/j.isci.2021.103273, doi:10.1016/j.isci.2021.103273. This article has 24 citations and is from a peer-reviewed journal.
(tahmaz2022prefoldinfunctionin pages 2-3): Ismail Tahmaz, Somayeh Shahmoradi Ghahe, and Ulrike Topf. Prefoldin function in cellular protein homeostasis and human diseases. Frontiers in Cell and Developmental Biology, Jan 2022. URL: https://doi.org/10.3389/fcell.2021.816214, doi:10.3389/fcell.2021.816214. This article has 48 citations and is from a poor quality or predatory journal.
(payanbravo2021humanprefoldinmodulates pages 1-4): Laura Payán-Bravo, Sara Fontalva, Xenia Peñate, Ildefonso Cases, José Antonio Guerrero-Martínez, Yerma Pareja-Sánchez, Yosu Odriozola-Gil, Esther Lara, Silvia Jimeno-González, Carles Suñé, Mari Cruz Muñoz-Centeno, José C. Reyes, and Sebastián Chávez. Human prefoldin modulates co-transcriptional pre-mrna splicing. Nucleic Acids Research, 49:6267-6280, Jun 2021. URL: https://doi.org/10.1101/2020.06.14.150466, doi:10.1101/2020.06.14.150466. This article has 13 citations and is from a highest quality peer-reviewed journal.
(fabian2024dipmsultradeepinteraction pages 7-8): Fabian Frommelt, Andrea Fossati, Federico Uliana, Fabian Wendt, Peng Xue, Moritz Heusel, Bernd Wollscheid, Ruedi Aebersold, Rodolfo Ciuffa, and Matthias Gstaiger. Dip-ms: ultra-deep interaction proteomics for the deconvolution of protein complexes. Nature Methods, 21:635-647, Mar 2024. URL: https://doi.org/10.1038/s41592-024-02211-y, doi:10.1038/s41592-024-02211-y. This article has 26 citations and is from a highest quality peer-reviewed journal.

Citations

herranzmontoya2021acomprehensiveanalysis pages 1-2
tahmaz2022prefoldinfunctionin pages 1-2
chesnel2020theprefoldincomplex pages 1-2
payanbravo2021humanprefoldinmodulates pages 1-4
fabian2024dipmsultradeepinteraction pages 7-8
herranzmontoya2021acomprehensiveanalysis pages 5-7
tahmaz2022prefoldinfunctionin pages 2-3
https://doi.org/10.1016/j.isci.2021.103273
https://doi.org/10.3389/fcell.2021.816214
https://doi.org/10.1371/journal.pgen.1009183
https://doi.org/10.1016/j.isci.2021.103273;
https://doi.org/10.1101/2020.06.14.150466
https://doi.org/10.1038/s41592-024-02211-y
https://doi.org/10.1038/s41592-024-02211-y;
https://doi.org/10.3389/fcell.2021.816214;
https://doi.org/10.1016/j.isci.2021.103273,
https://doi.org/10.3389/fcell.2021.816214,
https://doi.org/10.1371/journal.pgen.1009183,
https://doi.org/10.1101/2020.06.14.150466,
https://doi.org/10.1038/s41592-024-02211-y,

📄 View Raw YAML

id: Q9UHV9
gene_symbol: PFDN2
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Prefoldin subunit 2 (PFDN2) is a beta-class subunit of the canonical heterohexameric prefoldin
  co-chaperone complex (2 alpha + 4 beta subunits). Prefoldin functions as an ATP-independent
  holdase that captures nascent or unfolded polypeptides, principally actin and tubulin, and
  delivers them to the group II chaperonin TRiC/CCT for ATP-dependent folding. PFDN2 also
  participates in the PAQosome (prefoldin-like/R2TP complex) involved in biogenesis of
  multisubunit complexes. Beyond cytosolic proteostasis, PFDN2 localizes to the nucleus where
  the prefoldin complex supports transcription elongation and co-transcriptional splicing.
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for cytoplasm localization. Prefoldin is a cytosolic chaperone complex;
      PFDN2 functions primarily in the cytoplasm where it captures nascent actin and tubulin
      and delivers them to TRiC/CCT (PMID:9630229). Experimental evidence from PMID:16876117
      and PMID:17936702 confirms cytoplasmic localization by immunofluorescence.
    action: ACCEPT
    reason: >-
      Core localization. The IBA annotation is phylogenetically supported and confirmed by
      multiple experimental studies showing cytoplasmic localization of PFDN2.
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin."
      - reference_id: PMID:16876117
        supporting_text: "Prefoldin 2 is a subunit of a hexameric molecular chaperone complex, named prefoldin, which delivers nascent actin and tubulin proteins to the eukaryotic cytosolic chaperonin for facilitated folding."

- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein folding. Prefoldin is a co-chaperone that participates in protein
      folding by capturing unfolded substrates and delivering them to TRiC/CCT (PMID:9630229,
      PMID:30955883). Well-established core function.
    action: ACCEPT
    reason: >-
      Core biological process for prefoldin. The IBA is phylogenetically well-supported and
      consistent with extensive biochemical evidence for prefoldin's role in protein folding.
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins."
      - reference_id: PMID:30955883
        supporting_text: "The supra-chaperone assembly formed by PFD and TRiC is essential to prevent toxic conformations and ensure effective cellular proteostasis."

- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      IBA annotation for protein folding chaperone molecular function. GO:0044183 is defined
      as "Binding to a protein or a protein-containing complex to assist the protein folding
      process." This precisely describes prefoldin's holdase function - binding unfolded
      substrates and transferring them to TRiC/CCT (PMID:9630229, PMID:30955883).
    action: ACCEPT
    reason: >-
      This is the correct and most appropriate MF term for prefoldin subunits. Prefoldin
      acts as a holdase/transfer chaperone, binding unfolded actin and tubulin and delivering
      them to TRiC/CCT. The IBA is well-supported phylogenetically.
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it."
      - reference_id: PMID:30955883
        supporting_text: "PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles."

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for nuclear localization based on UniProt subcellular location mapping.
      Nuclear localization of PFDN2 is supported by experimental evidence from PMID:17936702
      (immunofluorescence) and by functional studies showing prefoldin subunits on transcribed
      chromatin supporting RNAPII CTD phosphorylation and co-transcriptional splicing.
    action: ACCEPT
    reason: >-
      Although IEA, this is consistent with experimental data from PMID:17936702 and
      PMID:16876117 showing nuclear localization, plus functional evidence for nuclear
      roles in transcription/splicing.
    supported_by:
      - reference_id: PMID:17936702
        supporting_text: "URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for cytoplasm based on UniProt subcellular location mapping. Redundant
      with the IBA annotation for the same term but from a different source. Cytoplasmic
      localization is well-established experimentally.
    action: ACCEPT
    reason: >-
      Duplicates the IBA annotation but from IEA source. Both are valid. Cytoplasmic
      localization is well-supported.

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      IEA annotation for mitochondrial localization. PMID:17936702 identified PFDN2 interaction
      with URI1 in a mitochondrial context. This was confirmed by IDA evidence in the same
      dataset. Mitochondrial localization relates to the URI/PAQosome complex rather than
      canonical prefoldin function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization is experimentally supported (PMID:17936702) but relates
      to the URI1/PAQosome interaction rather than canonical prefoldin chaperone function.
      Not a core localization for prefoldin function.
    supported_by:
      - reference_id: PMID:17936702
        supporting_text: "URI represents a mitochondrial substrate of S6K1"

- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for protein folding based on InterPro domain mapping. Consistent with
      the IBA and IDA annotations for the same term. Prefoldin's role in protein folding
      is well-established.
    action: ACCEPT
    reason: >-
      Redundant with IBA and IDA annotations for the same term. The InterPro-based mapping
      is correct and consistent with the known function of prefoldin.

- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for prefoldin complex based on InterPro domain mapping. PFDN2 is a
      well-established component of the canonical prefoldin heterohexameric complex, confirmed
      by cryo-EM structures (PDB:6NR8, 7WU7) and biochemical studies (PMID:9630229, PMID:30955883).
    action: ACCEPT
    reason: >-
      Core cellular component. PFDN2 is a structural subunit of the prefoldin complex,
      confirmed by multiple structures and biochemical characterization.
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "We describe the discovery of a heterohexameric chaperone protein, prefoldin"

- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      IEA annotation from ARBA machine learning for generic protein-containing complex.
      This is technically correct but too general - PFDN2 is specifically part of the
      prefoldin complex (GO:0016272) which is already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Too generic. The more specific term GO:0016272 (prefoldin complex) is already annotated
      and better describes the actual complex membership. This parent term adds no information.

- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation for unfolded protein binding based on InterPro mapping. While prefoldin
      does bind unfolded proteins, the more informative and accurate MF term is GO:0044183
      (protein folding chaperone), which captures the functional role of binding unfolded
      substrates to assist folding, not merely binding them.
    action: MODIFY
    reason: >-
      GO:0051082 "unfolded protein binding" describes only the binding aspect. The correct
      MF term for prefoldin is GO:0044183 "protein folding chaperone" which captures the
      complete holdase/transfer chaperone function. The IBA already uses GO:0044183.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15923622
  review:
    summary: >-
      IPI protein binding from PMID:15923622 (Yart et al., 2005). This paper is about
      parafibromin (HRPT2) associating with PAF1 and RNAPII. The interaction with PFDN2
      may have been detected as part of a larger interactome study. The generic protein
      binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from a study focused on parafibromin/PAF1/RNAPII. Does not
      provide specific functional information about PFDN2. The term "protein binding"
      is uninformative per curation guidelines.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16876117
  review:
    summary: >-
      IPI protein binding from PMID:16876117 (Tsao et al., 2006). This study demonstrated
      that HCV F protein interacts with PFDN2 via yeast two-hybrid and co-immunoprecipitation.
      The interaction impedes PFDN1-PFDN2 interaction and perturbs tubulin cytoskeleton.
      While a genuine interaction, the generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding. The actual functional annotation from this paper (protein folding
      chaperone activity, positive regulation of cytoskeleton organization) is captured by
      other annotations from the same reference.
    supported_by:
      - reference_id: PMID:16876117
        supporting_text: "hepatitis C virus (HCV) F protein was found to interact with a cellular protein named prefoldin 2"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: >-
      IPI protein binding from large-scale mass spectrometry interactome study (Ewing et al., 2007).
      High-throughput interactome data. Generic protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from high-throughput interactome study. Uninformative per
      curation guidelines.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  review:
    summary: >-
      IPI protein binding from quantitative chaperone interaction network study (Taipale et al., 2014).
      While this study provides valuable context about PFDN2's position in the chaperone
      network, the generic protein binding term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from chaperone interactome study. The actual functional
      annotations from prefoldin studies are better captured by GO:0044183.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: >-
      IPI protein binding from large-scale interactome architecture study (Huttlin et al., 2017).
      High-throughput study. Generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from high-throughput interactome study. Uninformative.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: >-
      IPI protein binding from binary protein interactome reference map (Luck et al., 2020).
      High-throughput study. Generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from high-throughput interactome study. Uninformative.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: >-
      IPI protein binding from neurodegenerative disease protein interactome mapping study
      (Haenig et al., 2020). High-throughput study. Generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from high-throughput interactome study. Uninformative.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: >-
      IPI protein binding from dual proteome-scale network study. High-throughput study.
      Generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from high-throughput interactome study. Uninformative.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: >-
      IPI protein binding from multimodal cell maps study. High-throughput study.
      Generic term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding from high-throughput interactome study. Uninformative.

- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA annotation for nucleoplasm based on immunofluorescence data curation (HPA).
      Consistent with known nuclear roles of prefoldin subunits in transcription elongation
      and co-transcriptional splicing.
    action: ACCEPT
    reason: >-
      Supported by immunofluorescence data from HPA and consistent with nuclear functions
      of prefoldin in transcription/splicing regulation.

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA annotation for mitochondrion based on immunofluorescence data curation (HPA).
      Consistent with PMID:17936702 showing PFDN2 association with URI1 at mitochondria.
    action: KEEP_AS_NON_CORE
    reason: >-
      Mitochondrial localization is experimentally supported but is a non-core localization
      relating to URI/PAQosome function rather than canonical prefoldin chaperone activity.

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: >-
      IDA annotation for cytosol based on immunofluorescence data curation (HPA). Cytosol
      is the primary site of prefoldin's canonical co-chaperone function.
    action: ACCEPT
    reason: >-
      Core localization. Cytosol is where prefoldin performs its primary function of
      capturing nascent actin/tubulin and delivering to TRiC/CCT.

- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: NAS
  original_reference_id: PMID:31738558
  review:
    summary: >-
      NAS annotation for protein stabilization from PMID:31738558 (Cloutier et al., 2020).
      This paper describes ASDURF as a novel prefoldin-like subunit of the PAQosome, which
      includes PFDN2. The PAQosome is involved in biogenesis of protein complexes, which
      involves stabilization. Prefoldin's holdase activity does stabilize unfolded proteins
      against aggregation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Protein stabilization is a secondary consequence of prefoldin's holdase function.
      The primary function is better captured as protein folding chaperone. Stabilization
      is not incorrect but is a secondary effect rather than core function.

- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:32699605
  review:
    summary: >-
      NAS annotation for protein folding from the review by Liang et al. (2020) covering
      prefoldin functions and mechanisms. Consistent with core function.
    action: ACCEPT
    reason: >-
      Redundant with IBA and IDA annotations but from a review source. Protein folding
      is a core function of prefoldin.

- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:34761191
  review:
    summary: >-
      NAS annotation for protein folding from Herranz-Montoya et al. (2021) comprehensive
      analysis of prefoldins. Consistent with core function.
    action: ACCEPT
    reason: >-
      Redundant with other protein folding annotations. Consistent with the well-established
      core function of the prefoldin complex.

- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: NAS
  original_reference_id: PMID:34761191
  review:
    summary: >-
      NAS annotation for protein stabilization from Herranz-Montoya et al. (2021).
      Prefoldin stabilizes client proteins (e.g., VHL) against aggregation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Protein stabilization is a secondary consequence of prefoldin's holdase function,
      not the primary molecular activity. Core function is better captured as protein
      folding chaperone.

- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: NAS
  original_reference_id: PMID:29662061
  review:
    summary: >-
      NAS annotation for protein stabilization from PMID:29662061 (Martino et al., 2018).
      This paper is about RPAP3 providing a scaffold for coupling HSP90 to the R2TP
      co-chaperone complex. Relevant to the PAQosome context of PFDN2.
    action: KEEP_AS_NON_CORE
    reason: >-
      Relates to the R2TP/PAQosome complex stabilization function. Not a core function
      of PFDN2 in the canonical prefoldin complex.

- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      IDA annotation for protein folding from Gestaut et al. (2019) Cell paper. This
      landmark study used cryo-EM, crosslinking-MS, and biochemical approaches to show
      that prefoldin associates with TRiC/CCT through a conserved electrostatic interface,
      with PFD enhancing folding rate and yield while suppressing non-productive cycles.
    action: ACCEPT
    reason: >-
      Strong experimental evidence from a landmark Cell paper demonstrating the structural
      and functional basis for prefoldin-TRiC cooperation in protein folding.
    supported_by:
      - reference_id: PMID:30955883
        supporting_text: "PFD can act after TRiC bound its substrates to enhance the rate and yield of the folding reaction, suppressing non-productive reaction cycles."

- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      IDA annotation for prefoldin complex from Gestaut et al. (2019). Cryo-EM structures
      of the prefoldin-TRiC complex were resolved, directly demonstrating prefoldin complex
      architecture.
    action: ACCEPT
    reason: >-
      Strong structural evidence from cryo-EM demonstrating prefoldin complex structure
      in association with TRiC/CCT.
    supported_by:
      - reference_id: PMID:30955883
        supporting_text: "we integrate cryoelectron microscopy (cryo-EM), crosslinking-mass-spectrometry and biochemical and cellular approaches to elucidate the structural and functional interplay between TRiC/CCT and PFD."

- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: IDA
  original_reference_id: PMID:30955883
  review:
    summary: >-
      IDA annotation for unfolded protein binding from Gestaut et al. (2019). While prefoldin
      does bind unfolded proteins, the more accurate MF term is GO:0044183 (protein folding
      chaperone) which captures the complete functional role.
    action: MODIFY
    reason: >-
      GO:0051082 describes only the binding aspect. GO:0044183 "protein folding chaperone"
      better captures prefoldin's complete holdase/transfer function. The binding is in
      service of assisted folding, not binding per se.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:30955883
        supporting_text: >-
          PFD alternates between an open "latched" conformation and a closed "engaged"
          conformation that aligns the PFD-TRiC substrate binding chambers.

- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      IDA annotation for amyloid-beta binding from Sorgjerd et al. (2013). The study demonstrated
      that recombinant human prefoldin (hPFD) inhibits Abeta fibrillation and induces formation
      of less toxic Abeta oligomers. This is a property of the intact hexameric complex, not
      specific to PFDN2.
    action: KEEP_AS_NON_CORE
    reason: >-
      The study demonstrated Abeta binding as a property of the intact prefoldin complex.
      This is consistent with prefoldin's general holdase function against misfolded proteins.
      However, this is not a core physiological function but rather reflects the general
      anti-aggregation capacity of the complex.
    supported_by:
      - reference_id: PMID:23614719
        supporting_text: "we investigated the effect of recombinant human PFD (hPFD) on Abeta(1-42) aggregation in vitro and found that hPFD inhibited Abeta fibrillation and induced formation of soluble Abeta oligomers."

- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      IDA annotation for prefoldin complex from Sorgjerd et al. (2013). The study used
      recombinant human prefoldin complex to study Abeta interactions, confirming the
      hexameric complex assembly.
    action: ACCEPT
    reason: >-
      Confirms prefoldin complex formation with recombinant human subunits.

- term:
    id: GO:1905907
    label: negative regulation of amyloid fibril formation
  evidence_type: IDA
  original_reference_id: PMID:23614719
  review:
    summary: >-
      IDA annotation for negative regulation of amyloid fibril formation from Sorgjerd et al.
      (2013). The study showed hPFD inhibits Abeta fibrillation in vitro. This is a property
      of the intact complex and reflects the general anti-aggregation holdase function.
    action: KEEP_AS_NON_CORE
    reason: >-
      This reflects in vitro anti-aggregation activity of the prefoldin complex rather than
      a primary physiological function. It is a secondary consequence of the holdase activity.
      The annotation is not wrong but represents a non-core function.
    supported_by:
      - reference_id: PMID:23614719
        supporting_text: "hPFD inhibited Abeta fibrillation and induced formation of soluble Abeta oligomers. Interestingly, cell viability measurements...showed that Abeta oligomers formed by hPFD were 30-40% less toxic"

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:16876117
  review:
    summary: >-
      IDA annotation for nuclear localization from Tsao et al. (2006). The study used
      confocal immunofluorescence microscopy and showed PFDN2 in both nucleus and cytoplasm.
    action: ACCEPT
    reason: >-
      Experimental evidence (immunofluorescence) supports nuclear localization. Consistent
      with known nuclear roles of prefoldin in transcription and splicing regulation.
    supported_by:
      - reference_id: PMID:16876117
        supporting_text: "The interaction was confirmed by confocal immunofluorescence microscopy as well as coimmunoprecipitation experiments."

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16876117
  review:
    summary: >-
      IDA annotation for cytoplasm from Tsao et al. (2006). Immunofluorescence confirms
      cytoplasmic localization.
    action: ACCEPT
    reason: >-
      Core localization confirmed by experimental immunofluorescence data. Consistent
      with canonical cytosolic chaperone function.

- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IPI
  original_reference_id: PMID:16876117
  review:
    summary: >-
      IPI annotation for protein folding chaperone from Tsao et al. (2006). The study showed
      PFDN2 interacts with HCV F protein, and that this interaction impedes PFDN1-PFDN2
      interaction and perturbs tubulin cytoskeleton. This demonstrates PFDN2's role as a
      chaperone for tubulin folding.
    action: ACCEPT
    reason: >-
      Demonstrates PFDN2's chaperone function via perturbation - HCV F protein interaction
      with PFDN2 disrupts prefoldin complex assembly and impairs tubulin folding, confirming
      PFDN2's role as a protein folding chaperone.
    supported_by:
      - reference_id: PMID:16876117
        supporting_text: "expression of HCV F protein impeded the interaction between prefoldin 1 and 2...expression of HCV F protein resulted in aberrant organization of tubulin cytoskeleton."

- term:
    id: GO:0051495
    label: positive regulation of cytoskeleton organization
  evidence_type: IDA
  original_reference_id: PMID:16876117
  review:
    summary: >-
      IDA annotation for positive regulation of cytoskeleton organization from Tsao et al.
      (2006). The study showed that disruption of PFDN2 function (by HCV F protein) leads
      to aberrant tubulin cytoskeleton organization, implying PFDN2 normally promotes
      proper cytoskeleton organization through its chaperone activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      While the study demonstrates that PFDN2 is required for proper cytoskeleton organization,
      this is a downstream consequence of its chaperone function (folding actin and tubulin)
      rather than a direct regulatory role. The annotation captures a true biological effect
      but the mechanism is indirect through protein folding.
    supported_by:
      - reference_id: PMID:16876117
        supporting_text: "expression of HCV F protein resulted in aberrant organization of tubulin cytoskeleton"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17936702
  review:
    summary: >-
      IPI protein binding from Djouder et al. (2007). This study showed PFDN2 interaction
      with URI1 in a phosphorylation-dependent manner. Generic protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Generic protein binding. The interaction with URI1 is more specifically captured
      by the PAQosome/prefoldin complex annotations.

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:17936702
  review:
    summary: >-
      IDA annotation for nuclear localization from Djouder et al. (2007). The study showed
      PFDN2 localizes to nucleus, cytoplasm, and mitochondria through immunofluorescence.
    action: ACCEPT
    reason: >-
      Experimental evidence for nuclear localization by immunofluorescence.

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17936702
  review:
    summary: >-
      IDA annotation for cytoplasm from Djouder et al. (2007). Confirmed by immunofluorescence.
    action: ACCEPT
    reason: >-
      Core localization confirmed experimentally.

- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:17936702
  review:
    summary: >-
      IDA annotation for mitochondrial localization from Djouder et al. (2007). PFDN2
      interacts with URI1 at mitochondria in a phosphorylation-dependent manner.
    action: KEEP_AS_NON_CORE
    reason: >-
      Experimentally supported mitochondrial localization, but this relates to the
      URI1/PAQosome interaction rather than canonical prefoldin chaperone function.
    supported_by:
      - reference_id: PMID:17936702
        supporting_text: "URI represents a mitochondrial substrate of S6K1"

- term:
    id: GO:0051082
    label: unfolded protein binding
  evidence_type: NAS
  original_reference_id: PMID:9630229
  review:
    summary: >-
      NAS annotation for unfolded protein binding from Vainberg et al. (1998), the original
      prefoldin discovery paper. While accurate that prefoldin binds unfolded proteins,
      GO:0044183 is the more appropriate MF term.
    action: MODIFY
    reason: >-
      GO:0051082 describes only the binding aspect. GO:0044183 "protein folding chaperone"
      better captures the complete holdase/transfer function described in this paper.
    proposed_replacement_terms:
      - id: GO:0044183
        label: protein folding chaperone
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "Prefoldin binds specifically to cytosolic chaperonin (c-cpn) and transfers target proteins to it."

- term:
    id: GO:0016272
    label: prefoldin complex
  evidence_type: NAS
  original_reference_id: PMID:9630229
  review:
    summary: >-
      NAS annotation for prefoldin complex from the original prefoldin discovery paper
      (Vainberg et al., 1998). Describes the heterohexameric complex architecture.
    action: ACCEPT
    reason: >-
      The foundational paper establishing the prefoldin complex. Core annotation.
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "We describe the discovery of a heterohexameric chaperone protein, prefoldin, based on its ability to capture unfolded actin."

- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:9630229
  review:
    summary: >-
      NAS annotation for protein folding from Vainberg et al. (1998). This paper established
      that prefoldin promotes protein folding by delivering substrates to c-CPN (TRiC/CCT).
    action: ACCEPT
    reason: >-
      Core function established in the original prefoldin paper.
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: "prefoldin promotes folding in an environment in which there are many competing pathways for nonnative proteins."

references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:15923622
  title: The HRPT2 tumor suppressor gene product parafibromin associates with human
    PAF1 and RNA polymerase II.
  findings: []
- id: PMID:16876117
  title: Interaction of hepatitis C virus F protein with prefoldin 2 perturbs tubulin
    cytoskeleton organization.
  findings:
    - statement: PFDN2 interacts with HCV F protein via yeast two-hybrid and co-IP
    - statement: HCV F protein impedes PFDN1-PFDN2 interaction
    - statement: Disruption leads to aberrant tubulin cytoskeleton organization
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:17936702
  title: S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates
    a negative feedback program that counters S6K1 survival signaling.
  findings:
    - statement: PFDN2 interacts with URI1 in phosphorylation-dependent manner
    - statement: PFDN2 localizes to nucleus, cytoplasm, and mitochondria
- id: PMID:23614719
  title: "Human prefoldin inhibits amyloid-\u03B2 (A\u03B2) fibrillation and contributes\
    \ to formation of nontoxic A\u03B2 aggregates."
  findings:
    - statement: Recombinant human prefoldin inhibits Abeta fibrillation
    - statement: hPFD induces formation of less toxic Abeta oligomers
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:29662061
  title: RPAP3 provides a flexible scaffold for coupling HSP90 to the human R2TP co-chaperone
    complex.
  findings: []
- id: PMID:30955883
  title: The Chaperonin TRiC/CCT Associates with Prefoldin through a Conserved Electrostatic
    Interface Essential for Cellular Proteostasis.
  findings:
    - statement: Cryo-EM structure of prefoldin-TRiC complex
    - statement: Conserved electrostatic interface between PFD and TRiC
    - statement: PFD enhances folding rate and yield
- id: PMID:31738558
  title: Upstream ORF-Encoded ASDURF Is a Novel Prefoldin-like Subunit of the PAQosome.
  findings:
    - statement: PFDN2 is a component of the PAQosome complex
    - statement: PAQosome contains prefoldin-like module with PFDN2 and PFDN6
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32699605
  title: The functions and mechanisms of prefoldin complex and prefoldin-subunits.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:34761191
  title: A comprehensive analysis of prefoldins and their implication in cancer.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: PMID:9630229
  title: Prefoldin, a chaperone that delivers unfolded proteins to cytosolic chaperonin.
  findings:
    - statement: Discovery of prefoldin as heterohexameric chaperone
    - statement: Prefoldin captures unfolded actin and delivers to cytosolic chaperonin
    - statement: Promotes folding in competitive environment
core_functions:
  - description: >-
      PFDN2 is a beta-type subunit of the heterohexameric prefoldin co-chaperone
      complex that captures unfolded nascent polypeptides (primarily actin and tubulin)
      and delivers them to the TRiC/CCT chaperonin for ATP-dependent folding. Disruption
      of PFDN1-PFDN2 interaction (e.g., by HCV F protein) leads to aberrant tubulin
      cytoskeleton organization, confirming the functional importance of PFDN2 in
      cytoskeletal protein folding.
    molecular_function:
      id: GO:0044183
      label: protein folding chaperone
    directly_involved_in:
      - id: GO:0006457
        label: protein folding
    locations:
      - id: GO:0005829
        label: cytosol
    in_complex:
      id: GO:0016272
      label: prefoldin complex
    supported_by:
      - reference_id: PMID:9630229
        supporting_text: >-
          We describe the discovery of a heterohexameric chaperone protein, prefoldin,
          based on its ability to capture unfolded actin. Prefoldin binds specifically
          to cytosolic chaperonin (c-cpn) and transfers target proteins to it.
      - reference_id: PMID:30955883
        supporting_text: >-
          PFD can act after TRiC bound its substrates to enhance the rate and yield
          of the folding reaction, suppressing non-productive reaction cycles.
      - reference_id: PMID:16876117
        supporting_text: >-
          expression of HCV F protein impeded the interaction between prefoldin 1 and
          2...expression of HCV F protein resulted in aberrant organization of tubulin
          cytoskeleton.

PFDN2

Gene Description

Existing Annotations Review

Core Functions

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

Citations

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