Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006457 protein folding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: As a PPIase, PPIB accelerates proline-limited steps of protein folding; protein folding is a valid downstream process of its isomerase activity. Reason: Protein folding is the biological-process consequence of PPIB's peptidyl-prolyl isomerase molecular function rather than the function itself; appropriate as non-core. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt may therefore assist protein folding
GO:0016018 cyclosporin A binding	IBA GO_REF:0000033	ACCEPT	Summary: PPIB is a cyclophilin whose PPIase activity is inhibited by cyclosporin A; CsA binding is a defining property of the cyclophilin family and is structurally documented. Reason: Cyclosporin A binding is a genuine, structurally documented property of cyclophilin B (crystal structure with CsA) and the basis for inhibition of its PPIase activity. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt Inhibited by cyclosporin A (CsA).
GO:0003755 peptidyl-prolyl cis-trans isomerase activity	IEA GO_REF:0000120	ACCEPT	Summary: This is the core molecular function of PPIB - catalysis of peptidyl-proline cis-trans isomerization (EC 5.2.1.8, RHEA:16237). Reason: Matches PPIB's documented catalytic activity and is the central, experimentally validated function of cyclophilin B. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt EC=5.2.1.8
GO:0005788 endoplasmic reticulum lumen	IEA GO_REF:0000044	ACCEPT	Summary: PPIB is a soluble ER-lumenal protein with a C-terminal ER-retention motif; the precise core compartment. Reason: ER lumen is the documented localization, consistent with the retention motif and direct evidence. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0042470 melanosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: PPIB identified by mass spectrometry in melanosome fractions; a secondary localization. Reason: A proteomics-detected secondary localization, peripheral to the core ER-lumenal function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt Identified by mass spectrometry in melanosome fractions
GO:0005515 protein binding	IPI PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus...	KEEP AS NON CORE	Summary: Interaction with hepatitis C virus NS5B RNA polymerase (host-factor context). Bare protein binding is uninformative. Reason: A virus host-factor interaction; the generic protein binding term is uninformative and not part of PPIB's core PPIase function. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv UniProtKB:Q9WMX2-PRO_0000037552
GO:0005515 protein binding	IPI PMID:21280149 Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndro...	KEEP AS NON CORE	Summary: Interaction with DYM (dymeclin), relevant to bone/secretory-pathway biology. Bare protein binding is uninformative. Reason: A documented interaction (DYM), but the generic protein binding term is uninformative and not the core function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; Q7RTS9: DYM; NbExp=4; IntAct=EBI-359252, EBI-2871106;
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	KEEP AS NON CORE	Summary: Next-generation interactome dataset capturing a PPIB-SGTB (Q96EQ0) interaction. Bare protein binding is uninformative. Reason: High-throughput interaction; uninformative generic term, not part of the core function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; Q96EQ0: SGTB; NbExp=4; IntAct=EBI-359252, EBI-744081;
GO:0005515 protein binding	IPI PMID:22665516 An interaction map of endoplasmic reticulum chaperones and f...	KEEP AS NON CORE	Summary: Interaction with ERp72/PDIA4 (P13667); PPIB and ERp72 form a functional module that accelerates IgG folding. The bare protein binding term is uninformative but the interaction is biologically meaningful. Reason: A functionally meaningful ER foldase-complex interaction (ERp72/PDIA4), but the generic protein binding term is uninformative; the informative role is captured as PPIase and ER chaperone-complex membership. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; P13667: PDIA4; NbExp=2; IntAct=EBI-359252, EBI-1054653;
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale interactome capturing PPIB binary interactions (e.g. SGTA, PEX19, BANP, UBQLN1). Bare protein binding is uninformative. Reason: High-throughput binary interactions; uninformative generic term, not core. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; O43765: SGTA; NbExp=6; IntAct=EBI-359252, EBI-347996;
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	KEEP AS NON CORE	Summary: Crosslinking mass-spectrometry study capturing a PPIB-PDIA4 interaction. Bare protein binding is uninformative. Reason: Records the PDIA4 interaction again; generic term, not core. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; P13667: PDIA4; NbExp=2; IntAct=EBI-359252, EBI-1054653;
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Reference binary interactome capturing PPIB interactions (e.g. HSPA6/P17066, SGTA, PEX19). Bare protein binding is uninformative. Reason: High-throughput binary interactions; uninformative generic term, not core. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; P17066: HSPA6; NbExp=3; IntAct=EBI-359252, EBI-355106;
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegeneration interactome capturing PPIB binary interactions (e.g. HOXC4, ID2, STIM1). Bare protein binding is uninformative. Reason: High-throughput binary interactions with mostly unrelated partners; uninformative generic term, not core. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt P23284; P09017: HOXC4; NbExp=3; IntAct=EBI-359252, EBI-3923226;
GO:0005790 smooth endoplasmic reticulum	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Smooth-ER localization inferred from the rat ortholog; a sub-compartment refinement of the ER localization. Reason: A plausible ER sub-compartment annotation transferred by similarity; subsumed by the core ER/ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0034663 endoplasmic reticulum chaperone complex	IEA GO_REF:0000107	ACCEPT	Summary: PPIB is a component of a large ER chaperone/foldase multiprotein complex (with BiP, GRP94, PDIs, etc.); this localization/complex annotation is well supported. Reason: PPIB's membership in the ER chaperone complex is experimentally documented; the complex is the functional context for its foldase activity. Supporting Evidence: PMID:12475965 We demonstrate the existence of a large endoplasmic reticulum (ER)-localized multiprotein complex that is comprised of the molecular chaperones BiP; GRP94; CaBP1; protein disulfide isomerase (PDI); ERdj3, a recently identified ER Hsp40 cochaperone; cyclophilin B; ERp72; GRP170; UDP-glucosyltransferase; and SDF2-L1.
GO:0005515 protein binding	IPI PMID:39245686 The structural basis for the collagen processing by human P3...	KEEP AS NON CORE	Summary: Structural study of the P3H1/CRTAP/PPIB ternary complex (partner CRTAP/Q32P28) that processes collagen; the interaction is biologically central but the bare protein binding term is uninformative. Reason: A functionally important interaction (the collagen prolyl 3-hydroxylation complex), but the generic protein binding term is uninformative; the informative role is captured by the PPIase MF and collagen/bone process annotations. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv UniProtKB:Q32P28
GO:0005783 endoplasmic reticulum	IDA GO_REF:0000052	ACCEPT	Summary: Direct (immunofluorescence) evidence for ER localization. Reason: IDA-supported ER localization, consistent with the core ER-lumenal compartment. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0042470 melanosome	EXP PMID:17081065 Proteomic and bioinformatic characterization of the biogenes...	KEEP AS NON CORE	Summary: Mass-spectrometry detection of PPIB in melanosome fractions (stages I-IV). Reason: A genuine but secondary proteomics localization, peripheral to the core ER-lumenal function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt Identified by mass spectrometry in melanosome fractions
GO:0005829 cytosol	TAS Reactome:R-HSA-9728804	KEEP AS NON CORE	Summary: Reactome cytosol localization (likely a pathway/context assignment); not the principal compartment for this ER-lumenal protein. Reason: A curated localization for a specific pathway context; secondary to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005515 protein binding	IPI PMID:20147391 CD147/EMMPRIN acts as a functional entry receptor for measle...	KEEP AS NON CORE	Summary: Interaction with measles virus nucleoprotein (microbial-infection context; partner Q9WMB5). Bare protein binding is uninformative. Reason: A virus host-factor interaction; the generic protein binding term is uninformative and not part of the core function. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv UniProtKB:Q9WMB5
GO:0030593 neutrophil chemotaxis	IDA PMID:11688976 CD147 is a signaling receptor for cyclophilin B.	KEEP AS NON CORE	Summary: Secreted/extracellular cyclophilin B signals through CD147/EMMPRIN to promote neutrophil chemotaxis; a genuine but specialized extracellular role distinct from the ER foldase function. Reason: A documented extracellular signaling function of the secreted pool (via CD147), but distinct from and non-core relative to PPIB's ER PPIase activity. Supporting Evidence: PMID:11688976 CD147 is a signaling receptor for cyclophilin B.
GO:0005518 collagen binding	ISS GO_REF:0000024	ACCEPT	Summary: PPIB contributes to collagen binding within the prolyl 3-hydroxylation complex; collagen is a key substrate for its proline isomerization in collagen biogenesis. Reason: Collagen binding (contributes_to) is consistent with PPIB's role in the P3H1/CRTAP/PPIB complex acting on procollagen; supports its collagen-processing function. Supporting Evidence: PMID:39245686 collagen processing by human P3H1/CRTAP/PPIB ternary
GO:0003755 peptidyl-prolyl cis-trans isomerase activity	IDA PMID:20676357 Structural and biochemical characterization of the human cyc...	ACCEPT	Summary: Direct biochemical demonstration of PPIase activity for human cyclophilin B - the core molecular function. Reason: IDA-supported PPIase activity from biochemical characterization of the human cyclophilin family; the central function of PPIB. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds
GO:0044794 host-mediated activation of viral process	IMP PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus...	KEEP AS NON CORE	Summary: Cyclophilin B acts as a host factor regulating HCV RNA polymerase; a specialized virus-host process. Reason: A genuine but specialized host-factor role in viral replication; non-core relative to PPIB's ER PPIase function. Supporting Evidence: PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.
GO:0044829 host-mediated activation of viral genome replication	IMP PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus...	KEEP AS NON CORE	Summary: Cyclophilin B promotes HCV genome replication via NS5B; a specialized virus-host role. Reason: A documented but specialized host-factor function in viral genome replication; non-core relative to the ER PPIase function. Supporting Evidence: PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus...	KEEP AS NON CORE	Summary: Perinuclear localization observed in the HCV-host-factor study; a context-specific localization. Reason: A context-specific (viral replication) localization; secondary to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0070063 RNA polymerase binding	IPI PMID:15989969 Cyclophilin B is a functional regulator of hepatitis C virus...	KEEP AS NON CORE	Summary: Binding to HCV NS5B RNA-dependent RNA polymerase (a viral, not host, polymerase); a host-factor interaction rather than a general RNA polymerase binding function. Reason: The 'RNA polymerase binding' here reflects a specific interaction with the viral NS5B polymerase in a host-factor context, not a core cellular function of PPIB. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv UniProtKB:Q9WMX2-PRO_0000037552
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	KEEP AS NON CORE	Summary: High-throughput proteomics detection at focal adhesions; uninformative for this ER-lumenal protein. Reason: A proteomic-survey localization; secondary/peripheral to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: Exosome proteomics detection; consistent with a secreted pool but a high-throughput localization. Reason: PPIB has a secreted pool, so exosome detection is plausible, but it is secondary to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	KEEP AS NON CORE	Summary: Generic high-throughput membrane-proteome detection; uninformative for this soluble ER-lumenal protein. Reason: A generic proteomic localization; uninformative relative to the precise ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: Sperm-nucleus proteomics detection; a high-throughput localization not reflecting PPIB's principal compartment. Reason: A proteomic-survey localization (sperm nucleus); secondary/uninformative relative to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	MARK AS OVER ANNOTATED	Summary: High-throughput mRNA-interactome capture identified PPIB; likely a non-specific RNA-binding signal for this PPIase. Reason: Detection in mRNA-interactome capture does not establish a specific, functional RNA-binding role for cyclophilin B; over-annotation for an ER foldase. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv GO:0003723
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	MARK AS OVER ANNOTATED	Summary: A second high-throughput mRNA-interactome capture identified PPIB; same caveat as above. Reason: A non-specific RNA-binding signal from proteome-wide RNA-interactome capture; not an established functional activity of PPIB. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv GO:0003723
GO:0003755 peptidyl-prolyl cis-trans isomerase activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS-transferred PPIase activity, consistent with the experimentally validated core function. Reason: Corroborates the IDA-supported core PPIase molecular function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt EC=5.2.1.8
GO:0032991 protein-containing complex	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Generic 'protein-containing complex' membership; correct but uninformative relative to the specific ER chaperone complex annotation. Reason: PPIB is part of defined complexes, but this generic term is uninformative; the specific ER chaperone complex term is preferred. Supporting Evidence: PMID:12475965 We demonstrate the existence of a large endoplasmic reticulum (ER)-localized multiprotein complex that is comprised of the molecular chaperones BiP; GRP94; CaBP1; protein disulfide isomerase (PDI); ERdj3, a recently identified ER Hsp40 cochaperone; cyclophilin B; ERp72; GRP170; UDP-glucosyltransferase; and SDF2-L1.
GO:0005783 endoplasmic reticulum	IDA PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal...	ACCEPT	Summary: Direct evidence for ER localization in the osteogenesis imperfecta study. Reason: IDA-supported ER localization, consistent with the core ER compartment. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0006457 protein folding	IMP NOT PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal...	ACCEPT	Summary: This is a NOT (negated) annotation - in PPIB-null osteogenesis imperfecta, collagen folding is NORMAL, unlike P3H1/CRTAP deficiency which delays collagen folding. Thus PPIB is not required for the overall rate of collagen folding in this assay. Reason: Supported by the finding that PPIB-deficient OI has normal collagen folding (no folding delay), distinguishing it from P3H1/CRTAP loss; the NOT annotation appropriately records that PPIB is not required for that folding step. Supporting Evidence: PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
GO:0040018 positive regulation of multicellular organism growth	IMP PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal...	KEEP AS NON CORE	Summary: PPIB deficiency affects growth (osteogenesis imperfecta phenotype); a downstream organismal phenotype. Reason: An organism-level growth phenotype consequent to PPIB loss in bone; non-core relative to the PPIase molecular function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt Osteogenesis imperfecta 9 (OI9)
GO:0050821 protein stabilization	IMP PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal...	KEEP AS NON CORE	Summary: PPIB contributes to stabilization/processing of collagen; a downstream effect of its role in the collagen-processing complex. Reason: Protein stabilization is a downstream process outcome of PPIB's role in collagen biogenesis; non-core relative to its PPIase function. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt Osteogenesis imperfecta 9 (OI9)
GO:0060348 bone development	IMP PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal...	ACCEPT	Summary: PPIB loss-of-function causes osteogenesis imperfecta type IX; bone development is a genuine, disease-defining biological process for PPIB. Reason: Strongly supported by human genetics - recessive PPIB mutations cause OI9, establishing a core role in collagen biogenesis and bone development. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt Osteogenesis imperfecta 9 (OI9)
GO:1901873 regulation of post-translational protein modification	IMP NOT PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal...	ACCEPT	Summary: A NOT (negated) annotation - PPIB deficiency does not reduce collagen post-translational modification (e.g. prolyl 3-hydroxylation remains normal in the PPIB-null OI), distinguishing it from P3H1/CRTAP loss. Reason: Consistent with the finding that PPIB-null OI shows normal collagen folding/modification; the negation appropriately records that PPIB is not required for regulating this post-translational modification. Supporting Evidence: PMID:20089953 Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	KEEP AS NON CORE	Summary: Exosome proteomics detection (parotid gland); high-throughput localization consistent with a secreted pool. Reason: A proteomic-survey localization; secondary to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: Exosome proteomics detection (urinary exosomes); same caveat. Reason: A proteomic-survey localization; secondary to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0006457 protein folding	IDA PMID:22665516 An interaction map of endoplasmic reticulum chaperones and f...	KEEP AS NON CORE	Summary: PPIB (with ERp72/PDIA4) enhances the rate of IgG folding; protein folding is a downstream process of its PPIase/foldase role. Reason: A valid, directly supported folding-acceleration role, but downstream of the core PPIase molecular function. Supporting Evidence: PMID:22665516 ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: Exosome proteomics detection (B-cell exosomes); high-throughput localization. Reason: A proteomic-survey localization; secondary to the core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-1980233	ACCEPT	Summary: Reactome ER-lumen localization; correct and core. Reason: Consistent with the documented core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-2022073	ACCEPT	Summary: Reactome ER-lumen localization (collagen biosynthesis pathway); correct and core. Reason: Consistent with the core ER-lumen localization and PPIB's role in collagen biosynthesis. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-8948226	ACCEPT	Summary: Reactome ER-lumen localization; correct and core. Reason: Consistent with the documented core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-8948230	ACCEPT	Summary: Reactome ER-lumen localization; correct and core. Reason: Consistent with the documented core ER-lumen localization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005515 protein binding	IPI PMID:15095401 Identification of FHOD1-binding proteins and mechanisms of F...	KEEP AS NON CORE	Summary: Interaction captured for PPIB (partner Q9Y613/FHOD1). Bare protein binding is uninformative. Reason: A high-throughput interaction; the generic protein binding term is uninformative and not core. Supporting Evidence: file:human/PPIB/PPIB-goa.tsv UniProtKB:Q9Y613
GO:0003755 peptidyl-prolyl cis-trans isomerase activity	NAS PMID:2000394 Human cyclophilin B: a second cyclophilin gene encodes a pep...	ACCEPT	Summary: The founding characterization describing human cyclophilin B as a peptidyl-prolyl isomerase with a signal sequence. Reason: Supports the core PPIase molecular function from the original gene characterization. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds
GO:0005788 endoplasmic reticulum lumen	NAS PMID:1530944 S-cyclophilin is retained intracellularly via a unique COOH-...	ACCEPT	Summary: S-cyclophilin is retained intracellularly via a C-terminal sequence and colocalizes with calreticulin (ER lumen). Reason: Consistent with the core ER-lumen localization and the C-terminal retention motif. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
GO:0005783 endoplasmic reticulum	TAS PMID:2000394 Human cyclophilin B: a second cyclophilin gene encodes a pep...	ACCEPT	Summary: ER localization asserted in the founding characterization. Reason: TAS-supported ER localization from the original gene description. Supporting Evidence: file:human/PPIB/PPIB-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum lumen

Core Functions

ER-lumenal cyclophilin-type peptidyl-prolyl cis-trans isomerase that catalyzes the cis-trans isomerization of Xaa-Pro peptide bonds, accelerating proline-limited steps of protein folding (notably during collagen and immunoglobulin maturation).

Molecular Function:

peptidyl-prolyl cis-trans isomerase activity

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

file:human/PPIB/PPIB-uniprot.txt
PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds
PMID:20676357
Structural and biochemical characterization of the human cyclophilin family

Component of the P3H1/CRTAP/PPIB collagen prolyl 3-hydroxylation complex that processes procollagen in the ER; loss of PPIB causes osteogenesis imperfecta type IX, establishing a role in collagen biogenesis and bone development.

Molecular Function:

peptidyl-prolyl cis-trans isomerase activity

Cellular Locations:

endoplasmic reticulum lumen

Supporting Evidence:

PMID:39245686
collagen processing by human P3H1/CRTAP/PPIB ternary
file:human/PPIB/PPIB-uniprot.txt
Osteogenesis imperfecta 9 (OI9)

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11688976

CD147 is a signaling receptor for cyclophilin B.

Extracellular cyclophilin B signals through the cell-surface receptor CD147 to mediate effects including leukocyte chemotaxis.

PMID:15095401

Identification of FHOD1-binding proteins and mechanisms of FHOD1-regulated actin dynamics.

PMID:1530944

S-cyclophilin is retained intracellularly via a unique COOH-terminal sequence and colocalizes with the calcium storage protein calreticulin.

S-cyclophilin (PPIB) is retained intracellularly via a C-terminal sequence and colocalizes with calreticulin, i.e. is an ER-resident protein.

PMID:15989969

Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.

Cyclophilin B interacts with the HCV NS5B RNA-dependent RNA polymerase and functions as a host factor stimulating viral RNA replication.

PMID:17081065

Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

PMID:19946888

Defining the membrane proteome of NK cells.

PMID:2000394

Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence.

Human cyclophilin B (PPIB) is encoded by a second cyclophilin gene and is a peptidyl-prolyl isomerase bearing an N-terminal signal sequence (secretory/ER targeting).

PMID:20089953

Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.

Recessive PPIB (cyclophilin B) deficiency causes osteogenesis imperfecta without rhizomelia, and notably with normal collagen folding - unlike P3H1/CRTAP deficiency, which delays collagen folding - indicating PPIB is not required for the overall collagen folding rate.

PMID:20147391

CD147/EMMPRIN acts as a functional entry receptor for measles virus on epithelial cells.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:20676357

Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.

Biochemical and structural characterization confirms human cyclophilin B (PPIB) is a peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) inhibited by cyclosporin A.

PMID:21280149

Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndrome, encodes a protein integral to extracellular matrix and golgi organization and is associated with protein secretion pathways critical in bone development.

PMID:21423176

Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:22658674

Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

PMID:22665516

An interaction map of endoplasmic reticulum chaperones and foldases.

PPIB (cyclophilin B) forms an ERp72(PDIA4)-cyclophilin B complex that enhances the rate of immunoglobulin G folding, defining a functional ER foldase module.

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:30021884

Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

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

PMID:39245686

The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex.

PPIB (cyclophilin B) is a component of the human P3H1/CRTAP/PPIB ternary complex that processes collagen (prolyl 3-hydroxylation and prolyl isomerization).

Reactome:R-HSA-1980233

Reactome collagen-biosynthesis ER-lumen annotation for PPIB.

Reactome:R-HSA-2022073

Reactome collagen-biosynthesis ER-lumen annotation for PPIB.

Reactome:R-HSA-8948226

Reactome ER-lumen annotation for PPIB.

Reactome:R-HSA-8948230

Reactome ER-lumen annotation for PPIB.

Reactome:R-HSA-9728804

Reactome cytosol annotation for PPIB.

file:human/PPIB/PPIB-uniprot.txt

UniProt entry P23284 (PPIB_HUMAN), Peptidyl-prolyl cis-trans isomerase B

ER-lumenal cyclophilin-type peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) inhibited by cyclosporin A; part of ER chaperone complexes and the P3H1/CRTAP/PPIB collagen-processing complex; recessive mutations cause osteogenesis imperfecta type IX; also secreted/cell-surface and acts via CD147.

Suggested Experiments

Experiment: Separate-of-function PPIB mutants (catalytically dead PPIase vs complex-assembly mutants) expressed in PPIB-null cells, assaying collagen 3-hydroxylation, folding kinetics and secretion to dissect catalytic versus scaffolding contributions.

Experiment: Quantify and perturb the secreted/cell-surface cyclophilin B pool (e.g. CD147-blocking) in leukocyte chemotaxis and viral-replication assays to define the in vivo relevance of its extracellular functions.

📚 Additional Documentation

Notes

(PPIB-notes.md)

PPIB (cyclophilin B / CypB / CYPB) research notes

UniProt P23284. ER-lumenal peptidyl-prolyl cis-trans isomerase (PPIase), EC 5.2.1.8. Cyclophilin-type.

Core MF

PPIase: catalyzes cis-trans isomerization of proline imidic peptide bonds.
[file:human/PPIB/PPIB-uniprot.txt "PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and may therefore assist protein folding."]
[PMID:20676357 structural/biochem characterization of human cyclophilin family PPIases; IDA PPIase activity; inhibited by CsA]
Cyclosporin A binding (GO:0016018) - cyclophilins bind CsA. Crystal structure with CsA (1CYN).

Localization

ER lumen; retained via C-terminal retention motif (213-216).
[file "SUBCELLULAR LOCATION: Endoplasmic reticulum lumen."]
Also secreted (S-cyclophilin/SCYLP), melanosome, exosomes, cell surface. Originally described as secreted cyclophilin.

Biology

Collagen folding / prolyl isomerization: part of P3H1/CRTAP/PPIB prolyl 3-hydroxylation complex.
PMID:39245686
Osteogenesis imperfecta type IX (OI9): autosomal recessive, caused by PPIB mutations.
[file "Osteogenesis imperfecta 9 (OI9)"]
Interesting: PPIB-null OI has NORMAL collagen folding (unlike P3H1/CRTAP), i.e. PPIB loss does not delay overall collagen folding rate -> the NOT|protein folding IMP (PMID:20089953).
PMID:20089953
ERp72(PDIA4)-cyclophilin B complex enhances IgG folding rate.
PMID:22665516
Part of large ER chaperone complex (PMID:12475965).
CD147/EMMPRIN signaling receptor -> neutrophil chemotaxis (secreted CypB). PMID:11688976
Host factor for HCV RNA polymerase (NS5B), measles virus. PMID:15989969

Action plan

PPIase activity (GO:0003755) IDA/IEA/ISS/NAS - ACCEPT (CORE MF).
cyclosporin A binding (GO:0016018) IBA - ACCEPT (cyclophilin signature; non-core but real).
ER / ER lumen / ER chaperone complex - ACCEPT.
melanosome / cytosol / exosome / focal adhesion / nucleus / membrane / perinuclear / smooth ER - KEEP_AS_NON_CORE (secondary/HT proteomics).
protein binding (many IPI HT) - KEEP_AS_NON_CORE; DYM, PDIA4 functionally meaningful but generic term.
collagen binding (GO:0005518) ISS contributes_to - ACCEPT/KEEP_AS_NON_CORE (collagen substrate; core-related, contributes_to). Keep as supporting core.
protein folding (GO:0006457) IBA/IDA (PMID:22665516) - KEEP_AS_NON_CORE (assists folding; downstream).
NOT|protein folding IMP (PMID:20089953) - ACCEPT (PPIB-null has normal collagen folding -> PPIB not required for general collagen folding rate; nuanced but valid negation).
NOT|regulation of post-translational protein modification (GO:1901873) IMP - ACCEPT (PPIB-null doesn't reduce collagen 3-hydroxylation per that paper; valid negation).
bone development (GO:0060348) IMP - ACCEPT (OI9; core BP).
protein stabilization (GO:0050821) IMP - KEEP_AS_NON_CORE.
pos reg organism growth (GO:0040018) IMP - KEEP_AS_NON_CORE.
neutrophil chemotaxis (GO:0030593) IDA - KEEP_AS_NON_CORE (secreted CypB/CD147 role).
host-mediated viral process/genome replication (GO:0044794/0044829) IMP - KEEP_AS_NON_CORE (HCV host factor).
RNA polymerase binding (GO:0070063) / RNA binding (GO:0003723) HDA/IPI - KEEP_AS_NON_CORE (HCV NS5B / HT RNA-interactome; RNA binding likely non-specific).
protein-containing complex (GO:0032991) ISS - KEEP_AS_NON_CORE (generic).
Core MF: peptidyl-prolyl cis-trans isomerase activity (GO:0003755); core BP collagen folding/bone development.

Pn Notes

(PPIB-pn-notes.md)

PPIB PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: P23284
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07b
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/PPIB/PPIB-ai-review.yaml
AIGR review HTML: present - genes/human/PPIB/PPIB-ai-review.html
Gene notes: present - genes/human/PPIB/PPIB-notes.md
GOA TSV: present - genes/human/PPIB/PPIB-goa.tsv
UniProt record: present - genes/human/PPIB/PPIB-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/PPIB.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/PPIB.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: PPIB (peptidyl-prolyl cis-trans isomerase B; cyclophilin B / CypB; also called S-cyclophilin/SCYLP and rotamase B) is an endoplasmic reticulum-lumenal cyclophilin-type peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) that catalyzes the rate-limiting cis-trans isomerization of Xaa-Pro peptide bonds and thereby accelerates protein folding. It is retained in the ER lumen by a C-terminal retention motif and is a component of ER chaperone/foldase complexes, including the prolyl 3-hydroxylation complex with P3H1 (LEPRE1) and CRTAP that processes procollagen, and an ERp72(PDIA4)-cyclophilin B module that accelerates immunoglobulin folding. Loss-of-function mutations in PPIB cause autosomal-recessive osteogenesis imperfecta type IX, underscoring its role in collagen biogenesis and bone development. Beyond the ER, a secreted/cell-surface pool of cyclophilin B signals through the receptor CD147/EMMPRIN to promote leukocyte (neutrophil) chemotaxis, and the protein is exploited as a host factor by certain viruses (e.g. hepatitis C virus NS5B polymerase, measles virus). Its PPIase activity is inhibited by the immunosuppressant cyclosporin A.
Existing/core annotation action counts: ACCEPT: 19; KEEP_AS_NON_CORE: 32; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

Consistency: Fully consistent. Review, notes, and UniProt agree PPIB is a genuine ER-lumenal cyclophilin-type PPIase (EC 5.2.1.8, CsA-inhibited) and a component of the P3H1/CRTAP/PPIB collagen prolyl-3-hydroxylation complex; LoF causes osteogenesis imperfecta type IX. Both PN mappings align with the review's two core functions.
PN story / NEW pressure: Two projections. (1) GO:0003755 (VERIFIED real) is already in GOA exact (IEA/IDA/ISS/NAS — confirmed in goa.tsv) and ACCEPTed as core — already captured, correct. (2) GO:0032964 collagen biosynthetic process (VERIFIED real via OLS) is NOT in PPIB GOA (confirmed: GOA has only collagen binding GO:0005518 and bone development GO:0060348) — a defensible NEW BP capturing PPIB's collagen-maturation role. Conclude: GO:0003755 already captured; GO:0032964 = ADD (defensible, real, novel-to-GOA).
Evidence alignment: PN node carries no reference titles, but review evidence directly supports both stories: PMID:20676357 / PMID:2000394 (PPIase activity, VERIFIED), PMID:39245686 (P3H1/CRTAP/PPIB collagen complex) and PMID:20089953 (PPIB-null OI) for the collagen/bone biology. Note the nuanced NOT|protein folding and NOT|regulation of PTM (PMID:20089953: PPIB-null OI has normal collagen folding) — these qualify, but do not contradict, the broader collagen-biosynthesis role.
Verdict: CONSISTENT — GO:0003755 already captured (correct); GO:0032964 is a sound NEW addition. Recommended edits: [YAML] consider adding GO:0032964 collagen biosynthetic process (involved_in) to PPIB existing/proposed terms, supported by PMID:39245686 + OI9 genetics, to align the review with the defensible PN projection.

Full Consistency Review

UniProt: P23284 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE (exhaustive; ~55 annotations, notes present, no provider deep-research file)
PN placement (2 rows): ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|Cyclophilin type and ER proteostasis|Maturation and folding of specific substrates|ER collagen processing and folding ; PN-node mapping: type+group (PPIases / Cyclophilin type)→GO:0003755 peptidyl-prolyl cis-trans isomerase activity (mapped/ok_for_propagation, already_in_goa_exact); collagen group→GO:0032964 collagen biosynthetic process (mapped/ok_for_propagation, new_to_goa); class/branch→no_mapping.
Consistency: Fully consistent. Review, notes, and UniProt agree PPIB is a genuine ER-lumenal cyclophilin-type PPIase (EC 5.2.1.8, CsA-inhibited) and a component of the P3H1/CRTAP/PPIB collagen prolyl-3-hydroxylation complex; LoF causes osteogenesis imperfecta type IX. Both PN mappings align with the review's two core functions.
PN story / NEW pressure: Two projections. (1) GO:0003755 (VERIFIED real) is already in GOA exact (IEA/IDA/ISS/NAS — confirmed in goa.tsv) and ACCEPTed as core — already captured, correct. (2) GO:0032964 collagen biosynthetic process (VERIFIED real via OLS) is NOT in PPIB GOA (confirmed: GOA has only collagen binding GO:0005518 and bone development GO:0060348) — a defensible NEW BP capturing PPIB's collagen-maturation role. Conclude: GO:0003755 already captured; GO:0032964 = ADD (defensible, real, novel-to-GOA).
Mapping strategy: Mappings are appropriately scoped — narrow, member-supported MF/BP terms, not over-broad umbrellas (unlike the TOMM20/HSPA8/RAB7A rejections). GO:0032964 is well-matched to PPIB's documented collagen-processing function and bone-disease genetics. No mapping change needed.
Evidence alignment: PN node carries no reference titles, but review evidence directly supports both stories: PMID:20676357 / PMID:2000394 (PPIase activity, VERIFIED), PMID:39245686 (P3H1/CRTAP/PPIB collagen complex) and PMID:20089953 (PPIB-null OI) for the collagen/bone biology. Note the nuanced NOT|protein folding and NOT|regulation of PTM (PMID:20089953: PPIB-null OI has normal collagen folding) — these qualify, but do not contradict, the broader collagen-biosynthesis role.
Verdict: CONSISTENT — GO:0003755 already captured (correct); GO:0032964 is a sound NEW addition. Recommended edits: [YAML] consider adding GO:0032964 collagen biosynthetic process (involved_in) to PPIB existing/proposed terms, supported by PMID:39245686 + OI9 genetics, to align the review with the defensible PN projection.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07b
review_yaml: genes/human/PPIB/PPIB-ai-review.yaml
PN workbook rows: 2

PN row 1: ER proteostasis | Folding enzyme | Peptidyl-prolyl isomerases | Cyclophilin type

UniProt: P23284
In branches: ER
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|Cyclophilin type
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0003755 peptidyl-prolyl cis-trans isomerase activity]
  rationale: This PN type denotes ER cyclophilin-family PPIases. The matching GO molecular function is appropriate for propagation.
- [group] ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0003755 peptidyl-prolyl cis-trans isomerase activity]
  rationale: This PN group is the ER peptidyl-prolyl isomerase family. The GO PPIase activity term is the appropriate propagation target for this folding enzyme bucket.
- [class] ER proteostasis|Folding enzyme
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: ER proteostasis | Maturation and folding of specific substrates | ER collagen processing and folding

UniProt: P23284
In branches: ER
PN-node mapping records (path + ancestors):
- [group] ER proteostasis|Maturation and folding of specific substrates|ER collagen processing and folding
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0032964 collagen biosynthetic process]
  rationale: This PN group contains ER factors dedicated to collagen maturation, processing, and folding. Collagen biosynthetic process captures the shared substrate-specific pathway context.
- [class] ER proteostasis|Maturation and folding of specific substrates
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (3)

GO:0003755 peptidyl-prolyl cis-trans isomerase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases
GO:0003755 peptidyl-prolyl cis-trans isomerase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Folding enzyme|Peptidyl-prolyl isomerases|Cyclophilin type
GO:0032964 collagen biosynthetic process | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Maturation and folding of specific substrates|ER collagen processing and folding

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: P23284
gene_symbol: PPIB
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PPIB (peptidyl-prolyl cis-trans isomerase B; cyclophilin B / CypB; also called S-cyclophilin/SCYLP and rotamase B) is an endoplasmic reticulum-lumenal cyclophilin-type peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) that catalyzes the rate-limiting cis-trans isomerization of Xaa-Pro peptide bonds and thereby accelerates protein folding. It is retained in the ER lumen by a C-terminal retention motif and is a component of ER chaperone/foldase complexes, including the prolyl 3-hydroxylation complex with P3H1 (LEPRE1) and CRTAP that processes procollagen, and an ERp72(PDIA4)-cyclophilin B module that accelerates immunoglobulin folding. Loss-of-function mutations in PPIB cause autosomal-recessive osteogenesis imperfecta type IX, underscoring its role in collagen biogenesis and bone development. Beyond the ER, a secreted/cell-surface pool of cyclophilin B signals through the receptor CD147/EMMPRIN to promote leukocyte (neutrophil) chemotaxis, and the protein is exploited as a host factor by certain viruses (e.g. hepatitis C virus NS5B polymerase, measles virus). Its PPIase activity is inhibited by the immunosuppressant cyclosporin A.
existing_annotations:
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: As a PPIase, PPIB accelerates proline-limited steps of protein folding; protein folding is a valid downstream process of its isomerase activity.
    action: KEEP_AS_NON_CORE
    reason: Protein folding is the biological-process consequence of PPIB's peptidyl-prolyl isomerase molecular function rather than the function itself; appropriate as non-core.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: may therefore assist protein folding
- term:
    id: GO:0016018
    label: cyclosporin A binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: PPIB is a cyclophilin whose PPIase activity is inhibited by cyclosporin A; CsA binding is a defining property of the cyclophilin family and is structurally documented.
    action: ACCEPT
    reason: Cyclosporin A binding is a genuine, structurally documented property of cyclophilin B (crystal structure with CsA) and the basis for inhibition of its PPIase activity.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: Inhibited by cyclosporin A (CsA).
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: This is the core molecular function of PPIB - catalysis of peptidyl-proline cis-trans isomerization (EC 5.2.1.8, RHEA:16237).
    action: ACCEPT
    reason: Matches PPIB's documented catalytic activity and is the central, experimentally validated function of cyclophilin B.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'EC=5.2.1.8'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: PPIB is a soluble ER-lumenal protein with a C-terminal ER-retention motif; the precise core compartment.
    action: ACCEPT
    reason: ER lumen is the documented localization, consistent with the retention motif and direct evidence.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: PPIB identified by mass spectrometry in melanosome fractions; a secondary localization.
    action: KEEP_AS_NON_CORE
    reason: A proteomics-detected secondary localization, peripheral to the core ER-lumenal function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: Identified by mass spectrometry in melanosome fractions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15989969
  qualifier: enables
  review:
    summary: Interaction with hepatitis C virus NS5B RNA polymerase (host-factor context). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A virus host-factor interaction; the generic protein binding term is uninformative and not part of PPIB's core PPIase function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: UniProtKB:Q9WMX2-PRO_0000037552
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21280149
  qualifier: enables
  review:
    summary: Interaction with DYM (dymeclin), relevant to bone/secretory-pathway biology. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A documented interaction (DYM), but the generic protein binding term is uninformative and not the core function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; Q7RTS9: DYM; NbExp=4; IntAct=EBI-359252, EBI-2871106;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  qualifier: enables
  review:
    summary: Next-generation interactome dataset capturing a PPIB-SGTB (Q96EQ0) interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; uninformative generic term, not part of the core function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; Q96EQ0: SGTB; NbExp=4; IntAct=EBI-359252, EBI-744081;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22665516
  qualifier: enables
  review:
    summary: Interaction with ERp72/PDIA4 (P13667); PPIB and ERp72 form a functional module that accelerates IgG folding. The bare protein binding term is uninformative but the interaction is biologically meaningful.
    action: KEEP_AS_NON_CORE
    reason: A functionally meaningful ER foldase-complex interaction (ERp72/PDIA4), but the generic protein binding term is uninformative; the informative role is captured as PPIase and ER chaperone-complex membership.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; P13667: PDIA4; NbExp=2; IntAct=EBI-359252, EBI-1054653;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome capturing PPIB binary interactions (e.g. SGTA, PEX19, BANP, UBQLN1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions; uninformative generic term, not core.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; O43765: SGTA; NbExp=6; IntAct=EBI-359252, EBI-347996;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30021884
  qualifier: enables
  review:
    summary: Crosslinking mass-spectrometry study capturing a PPIB-PDIA4 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the PDIA4 interaction again; generic term, not core.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; P13667: PDIA4; NbExp=2; IntAct=EBI-359252, EBI-1054653;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Reference binary interactome capturing PPIB interactions (e.g. HSPA6/P17066, SGTA, PEX19). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions; uninformative generic term, not core.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; P17066: HSPA6; NbExp=3; IntAct=EBI-359252, EBI-355106;'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome capturing PPIB binary interactions (e.g. HOXC4, ID2, STIM1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput binary interactions with mostly unrelated partners; uninformative generic term, not core.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'P23284; P09017: HOXC4; NbExp=3; IntAct=EBI-359252, EBI-3923226;'
- term:
    id: GO:0005790
    label: smooth endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Smooth-ER localization inferred from the rat ortholog; a sub-compartment refinement of the ER localization.
    action: KEEP_AS_NON_CORE
    reason: A plausible ER sub-compartment annotation transferred by similarity; subsumed by the core ER/ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0034663
    label: endoplasmic reticulum chaperone complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  review:
    summary: PPIB is a component of a large ER chaperone/foldase multiprotein complex (with BiP, GRP94, PDIs, etc.); this localization/complex annotation is well supported.
    action: ACCEPT
    reason: PPIB's membership in the ER chaperone complex is experimentally documented; the complex is the functional context for its foldase activity.
    supported_by:
    - reference_id: PMID:12475965
      supporting_text: >-
        We demonstrate the existence of a large endoplasmic reticulum (ER)-localized
        multiprotein complex that is comprised of the molecular chaperones BiP; GRP94; CaBP1;
        protein disulfide isomerase (PDI); ERdj3, a recently identified ER Hsp40 cochaperone;
        cyclophilin B; ERp72; GRP170; UDP-glucosyltransferase; and SDF2-L1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39245686
  qualifier: enables
  review:
    summary: Structural study of the P3H1/CRTAP/PPIB ternary complex (partner CRTAP/Q32P28) that processes collagen; the interaction is biologically central but the bare protein binding term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A functionally important interaction (the collagen prolyl 3-hydroxylation complex), but the generic protein binding term is uninformative; the informative role is captured by the PPIase MF and collagen/bone process annotations.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: UniProtKB:Q32P28
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct (immunofluorescence) evidence for ER localization.
    action: ACCEPT
    reason: IDA-supported ER localization, consistent with the core ER-lumenal compartment.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: EXP
  original_reference_id: PMID:17081065
  qualifier: located_in
  review:
    summary: Mass-spectrometry detection of PPIB in melanosome fractions (stages I-IV).
    action: KEEP_AS_NON_CORE
    reason: A genuine but secondary proteomics localization, peripheral to the core ER-lumenal function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: Identified by mass spectrometry in melanosome fractions
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9728804
  qualifier: located_in
  review:
    summary: Reactome cytosol localization (likely a pathway/context assignment); not the principal compartment for this ER-lumenal protein.
    action: KEEP_AS_NON_CORE
    reason: A curated localization for a specific pathway context; secondary to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20147391
  qualifier: enables
  review:
    summary: Interaction with measles virus nucleoprotein (microbial-infection context; partner Q9WMB5). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A virus host-factor interaction; the generic protein binding term is uninformative and not part of the core function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: UniProtKB:Q9WMB5
- term:
    id: GO:0030593
    label: neutrophil chemotaxis
  evidence_type: IDA
  original_reference_id: PMID:11688976
  qualifier: involved_in
  review:
    summary: Secreted/extracellular cyclophilin B signals through CD147/EMMPRIN to promote neutrophil chemotaxis; a genuine but specialized extracellular role distinct from the ER foldase function.
    action: KEEP_AS_NON_CORE
    reason: A documented extracellular signaling function of the secreted pool (via CD147), but distinct from and non-core relative to PPIB's ER PPIase activity.
    supported_by:
    - reference_id: PMID:11688976
      supporting_text: CD147 is a signaling receptor for cyclophilin B.
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: contributes_to
  review:
    summary: PPIB contributes to collagen binding within the prolyl 3-hydroxylation complex; collagen is a key substrate for its proline isomerization in collagen biogenesis.
    action: ACCEPT
    reason: Collagen binding (contributes_to) is consistent with PPIB's role in the P3H1/CRTAP/PPIB complex acting on procollagen; supports its collagen-processing function.
    supported_by:
    - reference_id: PMID:39245686
      supporting_text: collagen processing by human P3H1/CRTAP/PPIB ternary
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IDA
  original_reference_id: PMID:20676357
  qualifier: enables
  review:
    summary: Direct biochemical demonstration of PPIase activity for human cyclophilin B - the core molecular function.
    action: ACCEPT
    reason: IDA-supported PPIase activity from biochemical characterization of the human cyclophilin family; the central function of PPIB.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds
- term:
    id: GO:0044794
    label: host-mediated activation of viral process
  evidence_type: IMP
  original_reference_id: PMID:15989969
  qualifier: involved_in
  review:
    summary: Cyclophilin B acts as a host factor regulating HCV RNA polymerase; a specialized virus-host process.
    action: KEEP_AS_NON_CORE
    reason: A genuine but specialized host-factor role in viral replication; non-core relative to PPIB's ER PPIase function.
    supported_by:
    - reference_id: PMID:15989969
      supporting_text: Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.
- term:
    id: GO:0044829
    label: host-mediated activation of viral genome replication
  evidence_type: IMP
  original_reference_id: PMID:15989969
  qualifier: involved_in
  review:
    summary: Cyclophilin B promotes HCV genome replication via NS5B; a specialized virus-host role.
    action: KEEP_AS_NON_CORE
    reason: A documented but specialized host-factor function in viral genome replication; non-core relative to the ER PPIase function.
    supported_by:
    - reference_id: PMID:15989969
      supporting_text: Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15989969
  qualifier: located_in
  review:
    summary: Perinuclear localization observed in the HCV-host-factor study; a context-specific localization.
    action: KEEP_AS_NON_CORE
    reason: A context-specific (viral replication) localization; secondary to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0070063
    label: RNA polymerase binding
  evidence_type: IPI
  original_reference_id: PMID:15989969
  qualifier: enables
  review:
    summary: Binding to HCV NS5B RNA-dependent RNA polymerase (a viral, not host, polymerase); a host-factor interaction rather than a general RNA polymerase binding function.
    action: KEEP_AS_NON_CORE
    reason: The 'RNA polymerase binding' here reflects a specific interaction with the viral NS5B polymerase in a host-factor context, not a core cellular function of PPIB.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: UniProtKB:Q9WMX2-PRO_0000037552
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  qualifier: located_in
  review:
    summary: High-throughput proteomics detection at focal adhesions; uninformative for this ER-lumenal protein.
    action: KEEP_AS_NON_CORE
    reason: A proteomic-survey localization; secondary/peripheral to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: Exosome proteomics detection; consistent with a secreted pool but a high-throughput localization.
    action: KEEP_AS_NON_CORE
    reason: PPIB has a secreted pool, so exosome detection is plausible, but it is secondary to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: Generic high-throughput membrane-proteome detection; uninformative for this soluble ER-lumenal protein.
    action: KEEP_AS_NON_CORE
    reason: A generic proteomic localization; uninformative relative to the precise ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: Sperm-nucleus proteomics detection; a high-throughput localization not reflecting PPIB's principal compartment.
    action: KEEP_AS_NON_CORE
    reason: A proteomic-survey localization (sperm nucleus); secondary/uninformative relative to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    summary: High-throughput mRNA-interactome capture identified PPIB; likely a non-specific RNA-binding signal for this PPIase.
    action: MARK_AS_OVER_ANNOTATED
    reason: Detection in mRNA-interactome capture does not establish a specific, functional RNA-binding role for cyclophilin B; over-annotation for an ER foldase.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: GO:0003723
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22681889
  qualifier: enables
  review:
    summary: A second high-throughput mRNA-interactome capture identified PPIB; same caveat as above.
    action: MARK_AS_OVER_ANNOTATED
    reason: A non-specific RNA-binding signal from proteome-wide RNA-interactome capture; not an established functional activity of PPIB.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: GO:0003723
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ISS-transferred PPIase activity, consistent with the experimentally validated core function.
    action: ACCEPT
    reason: Corroborates the IDA-supported core PPIase molecular function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'EC=5.2.1.8'
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Generic 'protein-containing complex' membership; correct but uninformative relative to the specific ER chaperone complex annotation.
    action: KEEP_AS_NON_CORE
    reason: PPIB is part of defined complexes, but this generic term is uninformative; the specific ER chaperone complex term is preferred.
    supported_by:
    - reference_id: PMID:12475965
      supporting_text: >-
        We demonstrate the existence of a large endoplasmic reticulum (ER)-localized
        multiprotein complex that is comprised of the molecular chaperones BiP; GRP94; CaBP1;
        protein disulfide isomerase (PDI); ERdj3, a recently identified ER Hsp40 cochaperone;
        cyclophilin B; ERp72; GRP170; UDP-glucosyltransferase; and SDF2-L1.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:20089953
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization in the osteogenesis imperfecta study.
    action: ACCEPT
    reason: IDA-supported ER localization, consistent with the core ER compartment.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:20089953
  qualifier: involved_in
  negated: true
  review:
    summary: This is a NOT (negated) annotation - in PPIB-null osteogenesis imperfecta, collagen folding is NORMAL, unlike P3H1/CRTAP deficiency which delays collagen folding. Thus PPIB is not required for the overall rate of collagen folding in this assay.
    action: ACCEPT
    reason: Supported by the finding that PPIB-deficient OI has normal collagen folding (no folding delay), distinguishing it from P3H1/CRTAP loss; the NOT annotation appropriately records that PPIB is not required for that folding step.
    supported_by:
    - reference_id: PMID:20089953
      supporting_text: Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
- term:
    id: GO:0040018
    label: positive regulation of multicellular organism growth
  evidence_type: IMP
  original_reference_id: PMID:20089953
  qualifier: involved_in
  review:
    summary: PPIB deficiency affects growth (osteogenesis imperfecta phenotype); a downstream organismal phenotype.
    action: KEEP_AS_NON_CORE
    reason: An organism-level growth phenotype consequent to PPIB loss in bone; non-core relative to the PPIase molecular function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'Osteogenesis imperfecta 9 (OI9)'
- term:
    id: GO:0050821
    label: protein stabilization
  evidence_type: IMP
  original_reference_id: PMID:20089953
  qualifier: involved_in
  review:
    summary: PPIB contributes to stabilization/processing of collagen; a downstream effect of its role in the collagen-processing complex.
    action: KEEP_AS_NON_CORE
    reason: Protein stabilization is a downstream process outcome of PPIB's role in collagen biogenesis; non-core relative to its PPIase function.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'Osteogenesis imperfecta 9 (OI9)'
- term:
    id: GO:0060348
    label: bone development
  evidence_type: IMP
  original_reference_id: PMID:20089953
  qualifier: involved_in
  review:
    summary: PPIB loss-of-function causes osteogenesis imperfecta type IX; bone development is a genuine, disease-defining biological process for PPIB.
    action: ACCEPT
    reason: Strongly supported by human genetics - recessive PPIB mutations cause OI9, establishing a core role in collagen biogenesis and bone development.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'Osteogenesis imperfecta 9 (OI9)'
- term:
    id: GO:1901873
    label: regulation of post-translational protein modification
  evidence_type: IMP
  original_reference_id: PMID:20089953
  qualifier: involved_in
  negated: true
  review:
    summary: A NOT (negated) annotation - PPIB deficiency does not reduce collagen post-translational modification (e.g. prolyl 3-hydroxylation remains normal in the PPIB-null OI), distinguishing it from P3H1/CRTAP loss.
    action: ACCEPT
    reason: Consistent with the finding that PPIB-null OI shows normal collagen folding/modification; the negation appropriately records that PPIB is not required for regulating this post-translational modification.
    supported_by:
    - reference_id: PMID:20089953
      supporting_text: Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  qualifier: located_in
  review:
    summary: Exosome proteomics detection (parotid gland); high-throughput localization consistent with a secreted pool.
    action: KEEP_AS_NON_CORE
    reason: A proteomic-survey localization; secondary to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: Exosome proteomics detection (urinary exosomes); same caveat.
    action: KEEP_AS_NON_CORE
    reason: A proteomic-survey localization; secondary to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IDA
  original_reference_id: PMID:22665516
  qualifier: involved_in
  review:
    summary: PPIB (with ERp72/PDIA4) enhances the rate of IgG folding; protein folding is a downstream process of its PPIase/foldase role.
    action: KEEP_AS_NON_CORE
    reason: A valid, directly supported folding-acceleration role, but downstream of the core PPIase molecular function.
    supported_by:
    - reference_id: PMID:22665516
      supporting_text: ERp72-cyclophilin B complex that enhances the rate of folding of immunoglobulin
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: Exosome proteomics detection (B-cell exosomes); high-throughput localization.
    action: KEEP_AS_NON_CORE
    reason: A proteomic-survey localization; secondary to the core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1980233
  qualifier: located_in
  review:
    summary: Reactome ER-lumen localization; correct and core.
    action: ACCEPT
    reason: Consistent with the documented core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2022073
  qualifier: located_in
  review:
    summary: Reactome ER-lumen localization (collagen biosynthesis pathway); correct and core.
    action: ACCEPT
    reason: Consistent with the core ER-lumen localization and PPIB's role in collagen biosynthesis.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948226
  qualifier: located_in
  review:
    summary: Reactome ER-lumen localization; correct and core.
    action: ACCEPT
    reason: Consistent with the documented core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948230
  qualifier: located_in
  review:
    summary: Reactome ER-lumen localization; correct and core.
    action: ACCEPT
    reason: Consistent with the documented core ER-lumen localization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15095401
  qualifier: enables
  review:
    summary: Interaction captured for PPIB (partner Q9Y613/FHOD1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A high-throughput interaction; the generic protein binding term is uninformative and not core.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-goa.tsv
      supporting_text: UniProtKB:Q9Y613
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: NAS
  original_reference_id: PMID:2000394
  qualifier: enables
  review:
    summary: The founding characterization describing human cyclophilin B as a peptidyl-prolyl isomerase with a signal sequence.
    action: ACCEPT
    reason: Supports the core PPIase molecular function from the original gene characterization.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: NAS
  original_reference_id: PMID:1530944
  qualifier: located_in
  review:
    summary: S-cyclophilin is retained intracellularly via a C-terminal sequence and colocalizes with calreticulin (ER lumen).
    action: ACCEPT
    reason: Consistent with the core ER-lumen localization and the C-terminal retention motif.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: TAS
  original_reference_id: PMID:2000394
  qualifier: located_in
  review:
    summary: ER localization asserted in the founding characterization.
    action: ACCEPT
    reason: TAS-supported ER localization from the original gene description.
    supported_by:
    - reference_id: file:human/PPIB/PPIB-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum lumen'
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11688976
  title: CD147 is a signaling receptor for cyclophilin B.
  findings:
  - statement: Extracellular cyclophilin B signals through the cell-surface receptor CD147 to mediate effects including leukocyte chemotaxis.
    reference_section_type: ABSTRACT
- id: PMID:15095401
  title: Identification of FHOD1-binding proteins and mechanisms of FHOD1-regulated actin dynamics.
  findings: []
- id: PMID:1530944
  title: S-cyclophilin is retained intracellularly via a unique COOH-terminal sequence and colocalizes with the calcium storage protein calreticulin.
  findings:
  - statement: S-cyclophilin (PPIB) is retained intracellularly via a C-terminal sequence and colocalizes with calreticulin, i.e. is an ER-resident protein.
    reference_section_type: ABSTRACT
- id: PMID:15989969
  title: Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.
  findings:
  - statement: Cyclophilin B interacts with the HCV NS5B RNA-dependent RNA polymerase and functions as a host factor stimulating viral RNA replication.
    reference_section_type: ABSTRACT
- id: PMID:17081065
  title: Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:2000394
  title: 'Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence.'
  findings:
  - statement: Human cyclophilin B (PPIB) is encoded by a second cyclophilin gene and is a peptidyl-prolyl isomerase bearing an N-terminal signal sequence (secretory/ER targeting).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches; original identification of PPIB as a peptidyl-prolyl isomerase (GO:0003755) with an ER/secretory signal sequence.
- id: PMID:20089953
  title: Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding.
  findings:
  - statement: Recessive PPIB (cyclophilin B) deficiency causes osteogenesis imperfecta without rhizomelia, and notably with normal collagen folding - unlike P3H1/CRTAP deficiency, which delays collagen folding - indicating PPIB is not required for the overall collagen folding rate.
    reference_section_type: ABSTRACT
- id: PMID:20147391
  title: CD147/EMMPRIN acts as a functional entry receptor for measles virus on epithelial cells.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
  findings: []
- id: PMID:20676357
  title: Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.
  findings:
  - statement: Biochemical and structural characterization confirms human cyclophilin B (PPIB) is a peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) inhibited by cyclosporin A.
    reference_section_type: RESULTS
- id: PMID:21280149
  title: Dymeclin, the gene underlying Dyggve-Melchior-Clausen syndrome, encodes a protein integral to extracellular matrix and golgi organization and is associated with protein secretion pathways critical in bone development.
  findings: []
- id: PMID:21423176
  title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
  findings: []
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:22665516
  title: An interaction map of endoplasmic reticulum chaperones and foldases.
  findings:
  - statement: PPIB (cyclophilin B) forms an ERp72(PDIA4)-cyclophilin B complex that enhances the rate of immunoglobulin G folding, defining a functional ER foldase module.
    reference_section_type: RESULTS
- id: PMID:22681889
  title: The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:30021884
  title: Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  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:39245686
  title: The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex.
  findings:
  - statement: PPIB (cyclophilin B) is a component of the human P3H1/CRTAP/PPIB ternary complex that processes collagen (prolyl 3-hydroxylation and prolyl isomerization).
    reference_section_type: ABSTRACT
- id: Reactome:R-HSA-1980233
  title: Reactome collagen-biosynthesis ER-lumen annotation for PPIB.
  findings: []
- id: Reactome:R-HSA-2022073
  title: Reactome collagen-biosynthesis ER-lumen annotation for PPIB.
  findings: []
- id: Reactome:R-HSA-8948226
  title: Reactome ER-lumen annotation for PPIB.
  findings: []
- id: Reactome:R-HSA-8948230
  title: Reactome ER-lumen annotation for PPIB.
  findings: []
- id: Reactome:R-HSA-9728804
  title: Reactome cytosol annotation for PPIB.
  findings: []
- id: file:human/PPIB/PPIB-uniprot.txt
  title: UniProt entry P23284 (PPIB_HUMAN), Peptidyl-prolyl cis-trans isomerase B
  findings:
  - statement: ER-lumenal cyclophilin-type peptidyl-prolyl cis-trans isomerase (EC 5.2.1.8) inhibited by cyclosporin A; part of ER chaperone complexes and the P3H1/CRTAP/PPIB collagen-processing complex; recessive mutations cause osteogenesis imperfecta type IX; also secreted/cell-surface and acts via CD147.
    reference_section_type: OTHER
core_functions:
- description: ER-lumenal cyclophilin-type peptidyl-prolyl cis-trans isomerase that catalyzes the cis-trans isomerization of Xaa-Pro peptide bonds, accelerating proline-limited steps of protein folding (notably during collagen and immunoglobulin maturation).
  molecular_function:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: file:human/PPIB/PPIB-uniprot.txt
    supporting_text: PPIase that catalyzes the cis-trans isomerization of proline imidic peptide bonds
  - reference_id: PMID:20676357
    supporting_text: Structural and biochemical characterization of the human cyclophilin family
- description: Component of the P3H1/CRTAP/PPIB collagen prolyl 3-hydroxylation complex that processes procollagen in the ER; loss of PPIB causes osteogenesis imperfecta type IX, establishing a role in collagen biogenesis and bone development.
  molecular_function:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  locations:
  - id: GO:0005788
    label: endoplasmic reticulum lumen
  supported_by:
  - reference_id: PMID:39245686
    supporting_text: collagen processing by human P3H1/CRTAP/PPIB ternary
  - reference_id: file:human/PPIB/PPIB-uniprot.txt
    supporting_text: 'Osteogenesis imperfecta 9 (OI9)'
proposed_new_terms: []
suggested_questions:
- question: Given that PPIB-null osteogenesis imperfecta has normal collagen folding, what is the precise non-redundant contribution of PPIB's PPIase activity within the P3H1/CRTAP/PPIB complex versus its scaffolding role?
- question: How is the partitioning of PPIB between its ER foldase pool and its secreted/CD147-signaling pool regulated, and how much do extracellular functions contribute to disease phenotypes?
suggested_experiments:
- description: Separate-of-function PPIB mutants (catalytically dead PPIase vs complex-assembly mutants) expressed in PPIB-null cells, assaying collagen 3-hydroxylation, folding kinetics and secretion to dissect catalytic versus scaffolding contributions.
- description: Quantify and perturb the secreted/cell-surface cyclophilin B pool (e.g. CD147-blocking) in leukocyte chemotaxis and viral-replication assays to define the in vivo relevance of its extracellular functions.

PPIB

Gene Description