CRYAB (alpha-crystallin B chain, also known as HSPB5) is a small heat shock protein that functions as a molecular chaperone with holdase activity. It binds partially denatured or destabilized proteins in an ATP-independent manner to prevent their aggregation, but unlike HSP70-family foldase chaperones, it does NOT actively refold substrates. CRYAB forms large polydisperse oligomeric complexes, typically of 10-40 subunits, and can hetero-oligomerize with CRYAA (HSPB4). The canonical sHSP architecture comprises a central alpha-crystallin domain (ACD) flanked by a variable N-terminal domain (NTD) and a short C-terminal domain (CTD); chaperone activity is tightly coupled to oligomeric assembly and dynamic subunit exchange (DOI:10.1038/s41467-024-54647-7). A conserved N-terminal IXI-like motif (NT-IXI) engages the ACD hydrophobic groove, and perturbation of this motif transforms native assemblies into reversible elongated helical fibrils, as resolved by cryo-EM (DOI:10.1038/s41467-024-54647-7). Stress-activated phosphorylation at Ser19/Ser45/Ser59 by p38 MAPK modulates oligomeric state; the p38-CRYAB(pS59) cascade is a stress-response module that can shift CRYAB condensates toward less dynamic, aggregate-prone states under pathological conditions (DOI:10.1016/j.isci.2024.109510, DOI:10.1172/jci163730). In the eye lens, CRYAB serves dual roles as a structural protein contributing to transparency and refractive index, and as a chaperone preventing aggregation of damaged crystallins. Outside the lens, it is highly expressed in cardiac and skeletal muscle where it associates with cytoskeletal elements including desmin intermediate filaments and titin at Z-bands and intercalated disks. CRYAB also functions as a mitochondrial chaperone and anti-apoptotic protein, binding pro-apoptotic factors Bax, Bcl-X(S), cytochrome c, and VDAC; the E105K mutation causing hereditary optic atrophy reduces these interactions and impairs mitochondrial OXPHOS assembly (DOI:10.1172/jci.insight.182209). CRYAB is secreted via extracellular vesicles and exerts paracrine effects including promotion of angiogenesis in cardiac contexts (DOI:10.1186/s13287-023-03468-4, DOI:10.1038/s42003-022-04402-9). Mutations in CRYAB cause myofibrillar myopathy, cataracts, dilated cardiomyopathy, restrictive cardiomyopathy, and hereditary optic atrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for negative regulation of apoptotic process, phylogenetically propagated across small heat shock protein family members (CRYAA, CRYAB, HSPB1). CRYAB has well-documented anti-apoptotic activity. It binds pro-apoptotic Bax and Bcl-X(S) to prevent their translocation from cytosol to mitochondria during staurosporine-induced apoptosis (PMID:14752512). This preserves mitochondrial integrity and blocks caspase-3 activation and PARP degradation. Reason: CRYAB is a bona fide anti-apoptotic protein. PMID:14752512 demonstrates that alpha-crystallins bind Bax and Bcl-X(S) both in vitro and in vivo, preventing their translocation to mitochondria. The IBA annotation is phylogenetically appropriate and reflects a well-established function of CRYAB beyond its lens chaperone role. This is a core function of CRYAB, particularly in cardiac and muscle contexts. Supporting Evidence: PMID:14752512 alphaA- and alphaB-crystallins prevent staurosporine-induced apoptosis through interactions with members of the Bcl-2 family. Using GST pulldown assays and coimmunoprecipitations, we demonstrated that alpha-crystallins bind to Bax and Bcl-X(S) both in vitro and in vivo. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasm localization, phylogenetically propagated across sHSP family. CRYAB is a predominantly cytoplasmic protein. Multiple IDA annotations from different studies (PMID:19464326, PMID:20587334, PMID:14752512) confirm cytoplasmic localization. UniProt lists cytoplasm as a primary subcellular location. Reason: Cytoplasm is the primary localization of CRYAB. This is confirmed by multiple independent IDA studies (PMID:19464326, PMID:20587334, PMID:14752512) and is consistent with its role as a cytoplasmic holdase chaperone. The IBA annotation is appropriate and well-supported. Supporting Evidence: PMID:19464326 Online databases did not accurately predict the sub-cellular distribution of all the HSPB members. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for nuclear localization. CRYAB has been shown to translocate to the nucleus during heat shock, where it resides in SC35 speckles (nuclear splicing speckles) (PMID:19464326). It can also accumulate in the nucleus when co-expressed with LBH (PMID:20587334). Multiple IDA annotations support this. Reason: Nuclear localization is confirmed by IDA evidence from PMID:19464326 and PMID:20587334. CRYAB translocates to the nucleus during heat stress and resides in SC35 speckles. This is a conditional/stress-dependent localization but is well-documented. The IBA annotation is appropriate. Supporting Evidence: PMID:19464326 Some members also show a dynamic, stress-induced translocation to SC35 splicing speckles. |
| GO:0009408 response to heat | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for response to heat. CRYAB is a small heat shock protein (HSPB5) that is upregulated during heat stress and translocates to the nucleus (PMID:19464326). Its chaperone activity in preventing protein aggregation is central to its role in the heat shock response. The IBA is propagated from multiple Drosophila and C. elegans HSP orthologs. Reason: Response to heat is a core function of CRYAB as a member of the small heat shock protein family. It is upregulated during heat stress and shows stress-induced nuclear translocation (PMID:19464326). The IBA annotation is phylogenetically appropriate and reflects the conserved heat stress response function of sHSPs. Supporting Evidence: PMID:19464326 Unlike HSPB1 and HSPB5, that chaperoned heat unfolded substrates and kept them folding competent, HSPB7 did not support refolding. |
| GO:0042026 protein refolding | IBA GO_REF:0000033 | MODIFY | Summary: IBA annotation for protein refolding, propagated from Drosophila sHSP orthologs. This is problematic for CRYAB specifically. While some sHSPs in other organisms may participate in protein refolding pathways (by passing substrates to foldase chaperones like HSP70), CRYAB itself is a holdase -- it prevents aggregation of denatured proteins but does NOT actively refold them. PMID:19464326 explicitly tested refolding activity: HSPB1 and HSPB5 chaperoned heat unfolded substrates and kept them folding competent, but the refolding itself depends on downstream HSP70/HSP40 machinery. The term protein refolding implies direct refolding activity which CRYAB does not have. Reason: CRYAB is a holdase chaperone that prevents aggregation but does NOT perform protein refolding. The IBA may be appropriate at the broader sHSP family level where some members participate in refolding pathways, but for CRYAB specifically, protein refolding is misleading. CRYAB keeps substrates in a folding-competent state for downstream foldases (PMID:19464326), which is better captured by GO:0050821 protein stabilization (already annotated via IMP from PMID:12235146). The annotation should be modified to better reflect holdase/protein stabilization activity rather than direct refolding. Proposed replacements: protein stabilization Supporting Evidence: PMID:19464326 HSPB1 and HSPB5, that chaperoned heat unfolded substrates and kept them folding competent, HSPB7 did not support refolding. PMID:16303126 the major lenticular protein chaperones, alpha A- and alpha B-crystallin, increased the solubility of the T5P gamma C-crystallin both in vitro and in transfected cells. |
| GO:0051082 unfolded protein binding | IBA GO_REF:0000033 | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). CRYAB/HSPB5 does bind partially denatured or destabilized proteins, but the term "unfolded protein binding" is problematic because it implies a simple binding function rather than the chaperone holdase activity that CRYAB performs. CRYAB acts as a molecular chaperone that suppresses aggregation of destabilized proteins in an ATP-independent manner (PMID:16303126), but unlike HSP70-family foldase chaperones, it does NOT actively refold substrates. The IBA annotation is phylogenetically propagated from sHSP family members, which is appropriate at the family level since small heat shock proteins share this holdase chaperone function. However, the term itself needs replacement. GO:0140309 "unfolded protein carrier activity" is the appropriate MF term for ATP-independent binding to unfolded or destabilized proteins to prevent their aggregation without active refolding. UniProt describes CRYAB as having "chaperone-like activity, preventing aggregation of various proteins under a wide range of stress conditions." Reason: GO:0051082 is now formally obsolete. CRYAB has well-documented chaperone-like holdase activity: alpha-crystallins (including CRYAB) increase the solubility of destabilized T5P gamma C-crystallin and reduce the size of its aggregates both in vitro and in transfected cells (PMID:16303126). However, CRYAB does NOT refold proteins -- it is a holdase, not a foldase. The appropriate MF replacement is GO:0140309 "unfolded protein holdase activity." GO:0050821 "protein stabilization" is appropriate as a BP term and is already annotated for CRYAB via PMID:12235146. Proposed replacements: unfolded protein carrier activity Supporting Evidence: PMID:16303126 the major lenticular protein chaperones, alpha A- and alpha B-crystallin, increased the solubility of the T5P gamma C-crystallin both in vitro and in transfected cells. More importantly, the size of the T5P gamma C-crystallin aggregates were also significantly reduced in the presence of the lenticular chaperones. file:human/CRYAB/CRYAB-deep-research-falcon.md These concepts are consistent with CRYAB being a small HSP chaperone/holdase, not an enzyme/transporter; therefore its βprimary functionβ is ATP-independent chaperoning of destabilized proteins and stress-protective regulation of proteostasis. |
| GO:0005198 structural molecule activity | IEA GO_REF:0000117 | MODIFY | Summary: IEA annotation from ARBA machine learning for structural molecule activity. CRYAB does indeed serve as a structural protein in the eye lens, contributing to transparency and refractive index. There is also an IDA annotation for this term from PMID:16303126. However, the more specific term GO:0005212 structural constituent of eye lens is also annotated and is more informative. This broader IEA annotation is acceptable as it also reflects the structural role in muscle (association with sarcomeric Z-discs and desmin filaments). Reason: Structural molecule activity is broader than needed for CRYAB. The lens structural role is captured more precisely by GO:0005212 "structural constituent of eye lens", while muscle/cytoskeletal contexts are better captured by cytoskeletal protein binding and localization annotations. Proposed replacements: structural constituent of eye lens |
| GO:0005212 structural constituent of eye lens | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from combined automated methods for structural constituent of eye lens. CRYAB is one of the major structural proteins of the eye lens. It contributes to lens transparency and refractive index. This is well-established from decades of crystallin research and is supported by the InterPro alpha-crystallin N-terminal domain annotation (IPR003090) and the UniProt eye lens protein keyword. Reason: CRYAB is a major structural protein of the vertebrate eye lens. This is a core function. The annotation is appropriate and well-supported by the established biology of alpha-crystallins as both structural lens proteins and molecular chaperones. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location mapping. UniProt annotates CRYAB as Secreted based on PMID:32272059, which showed CRYAB can be secreted via an unconventional TMED10-dependent pathway involving translocation to the ERGIC. Additionally, CRYAB is found in extracellular exosomes (PMID:23533145, PMID:19056867). The extracellular region annotation is therefore justified. Reason: CRYAB has been shown to be secreted via an unconventional protein secretion pathway involving TMED10 (PMID:32272059) and is found in extracellular exosomes (PMID:23533145). The IEA annotation correctly reflects the UniProt subcellular location annotation for Secreted. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location mapping for nucleus. This is a duplicate of the IBA annotation for nucleus, and is also supported by multiple IDA annotations (PMID:19464326, PMID:20587334). Nuclear localization is stress-dependent. Reason: This IEA annotation is consistent with the IBA and IDA evidence. CRYAB translocates to the nucleus during heat stress (PMID:19464326). The IEA correctly maps the UniProt subcellular location annotation. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from combined automated methods for cytoplasm localization. CRYAB is primarily a cytoplasmic protein, confirmed by multiple IDA annotations (PMID:19464326, PMID:20587334, PMID:14752512) and the IBA annotation. Reason: This is redundant with the IBA and IDA annotations but is a correct broader IEA annotation. Cytoplasm is the primary localization of CRYAB. |
| GO:0005764 lysosome | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation from UniProt subcellular location mapping. UniProt annotates CRYAB as localizing to the lysosome based on similarity to the mouse ortholog P23927 (ECO:0000250). This is supported by PMID:31786107, which shows that CRYAB forms a complex with ATP6V1A and mTOR and regulates lysosome activity in lens epithelial cells. Reason: Lysosome localization is annotated by similarity to the mouse ortholog and is supported by the functional interaction between CRYAB, ATP6V1A (a lysosomal V-ATPase subunit) and mTOR (PMID:31786107). The IEA annotation is reasonable. |
| GO:0009892 negative regulation of metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: IEA annotation from ARBA machine learning for negative regulation of metabolic process. This is an extremely broad BP term. CRYAB does negatively regulate some metabolic processes (e.g., negative regulation of apoptosis, negative regulation of protein aggregation), but this term is too general to be informative. More specific terms are already annotated. Reason: This is an overly broad term that does not add useful information beyond what is captured by more specific annotations such as GO:0043066 negative regulation of apoptotic process and GO:0031333 negative regulation of protein-containing complex assembly. The ARBA prediction likely derives from the general chaperone/anti-apoptotic activities but is too unspecific. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation from UniProt keyword mapping for metal ion binding. CRYAB binds zinc ions through histidine residues (His-83, His-104, His-106, His-111, His-119) as documented in UniProt based on PMID:22890888. Zinc binding enhances oligomer stability. Reason: CRYAB has documented zinc-binding sites identified by chemical modification and MALDI-TOF mass spectrometry (PMID:22890888). Multiple histidine residues coordinate zinc ions, and this inter-subunit bridging enhances structural stability. The IEA annotation from the UniProt metal-binding keyword is appropriate. |
| GO:0005515 protein binding | IPI PMID:11700327 Detection of protein-protein interactions among lens crystal... | MARK AS OVER ANNOTATED | Summary: IPI annotation for protein binding from PMID:11700327 (Fu & Liang 2002), which used a mammalian two-hybrid system to detect interactions among lens crystallins. The WITH/FROM column in GOA lists interactions with CRYAA (P02489), HSPB1 (P04792), CRYGC (P07315), and CRYBB2 (P43320). These are genuine crystallin-crystallin interactions. However, protein binding is uninformative; the interactions with CRYAA are better captured by identical protein binding or the broader chaperone complex context. Reason: Protein binding is uninformative per GO curation guidelines. The interactions detected in PMID:11700327 (crystallin-crystallin interactions in mammalian two-hybrid assay) are real but are better captured by more specific terms such as identical protein binding (for self-interaction) or the chaperone function annotations. The binding to other crystallins reflects CRYAB's chaperone/structural role in the lens. |
| GO:0005515 protein binding | IPI PMID:12601044 Alteration of protein-protein interactions of congenital cat... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:12601044 (Fu & Liang 2003), which characterized altered protein-protein interactions of congenital cataract crystallin mutants using a mammalian two-hybrid system. Interactions detected include CRYAB with CRYAA, HSPB1, CRYGC, and CRYBB2. Reason: Protein binding is uninformative. The interactions described reflect crystallin-crystallin interactions relevant to lens function and are better captured by the identical protein binding and chaperone annotations. |
| GO:0005515 protein binding | IPI PMID:16049941 A pilot proteomic study of amyloid precursor interactors in ... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:16049941, a pilot proteomic study of amyloid precursor protein (APP, P05067) interactors in Alzheimer's disease. CRYAB was identified as an interactor of APP. Reason: Protein binding is uninformative. The interaction with APP is more specifically captured by the amyloid-beta binding annotation (GO:0001540) from PMID:23106396. |
| GO:0005515 protein binding | IPI PMID:17046756 alphaB-crystallin competes with Alzheimer's disease beta-amy... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:17046756 (Narayanan et al. 2006), which showed CRYAB competes for amyloid-beta peptide interactions using NMR spectroscopy. The WITH/FROM is CRYBA1 (P05813). The study demonstrated that CRYAB interactions involve the hydrophobic core residues of Abeta. Reason: Protein binding is uninformative. The interaction with amyloid-beta is better captured by GO:0001540 amyloid-beta binding (already annotated from PMID:23106396) and the negative regulation of amyloid fibril formation annotation. |
| GO:0005515 protein binding | IPI PMID:18330356 Construction and characterization of a normalized yeast two-... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:18330356, a large-scale normalized yeast two-hybrid library screen. The WITH/FROM is HSPB1 (P04792). CRYAB interaction with HSPB1 is well-established. Reason: Protein binding is uninformative. CRYAB-HSPB1 interaction is well-documented and reflects sHSP hetero-oligomer formation. This is better captured by the protein-containing complex and identical protein binding annotations. |
| GO:0005515 protein binding | IPI PMID:19651604 The eye lens chaperone alpha-crystallin forms defined globul... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:19651604 (Peschek et al. 2009), which showed that alpha-crystallin forms defined globular assemblies. The WITH/FROM is CRYAA (P02489), reflecting the CRYAB-CRYAA hetero-oligomerization. Reason: Protein binding is uninformative. The CRYAB-CRYAA interaction reflects hetero-oligomer formation and is better captured by the identical protein binding and protein-containing complex annotations. |
| GO:0005515 protein binding | IPI PMID:22085609 Temperature-dependent structural and functional properties o... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:22085609, which studied the F71L mutant alphaA-crystallin and its effects on hetero-oligomeric complex stability. The WITH/FROM is CRYAA (P02489). Reason: Protein binding is uninformative. This reflects CRYAB-CRYAA hetero-oligomerization. More specific annotations are already present. |
| GO:0005515 protein binding | IPI PMID:22153508 The polydispersity of Ξ±B-crystallin is rationalized by an in... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:22153508 (Baldwin et al. 2011), which elucidated the polyhedral architecture of CRYAB oligomers. The WITH/FROM is CRYAA (P02489). Reason: Protein binding is uninformative. This reflects CRYAB oligomerization dynamics. Better captured by identical protein binding and protein-containing complex annotations. |
| GO:0005515 protein binding | IPI PMID:22158051 Tumor suppressor Alpha B-crystallin (CRYAB) associates with ... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:22158051 (Huang et al. 2012), which showed CRYAB associates with the cadherin/catenin adherens junction. The WITH/FROM is beta-catenin (CTNNB1, P35222). CRYAB interacts with both E-cadherin and beta-catenin via its alpha-crystallin core domain, inhibiting E-cadherin internalization and NPC progression. Reason: Protein binding is uninformative. The specific interaction with beta-catenin described in PMID:22158051 reflects CRYAB's role in cell adhesion regulation in cancer context. This is a secondary/non-core function and the term protein binding does not capture the functional significance. |
| GO:0005515 protein binding | IPI PMID:23188086 Binding determinants of the small heat shock protein, Ξ±B-cry... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:23188086 (Delbecq et al. 2012), which studied the IxI motif binding determinants of CRYAB. The WITH/FROM includes CRYAA (P02489), HSPB1 (P04792), and HSPB2 (Q16082). Reason: Protein binding is uninformative. The IxI motif interactions are critical for sHSP oligomer assembly and are better captured by the identical protein binding and oligomerization-related annotations. |
| GO:0005515 protein binding | IPI PMID:23542032 Protective role of the endoplasmic reticulum protein mitsugu... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:23542032 (Yamashita et al. 2013), which identified CRYAB as a binding partner of mitsugumin23 (TMEM109/MG23, mouse Q3UBX0). The interaction mediates a protective role against UVC-induced cell death by accumulating CRYAB near the ER. Reason: Protein binding is uninformative. The CRYAB-TMEM109 interaction is functionally significant in the DNA damage response, but the protein binding term does not capture this. The functional role is partially captured by the regulation of programmed cell death annotation. |
| GO:0005515 protein binding | IPI PMID:24183572 Preferential and specific binding of human Ξ±B-crystallin to ... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:24183572 (Kingsley et al. 2013), which showed preferential and specific binding of CRYAB to the cataract-related G18V variant of gammaS-crystallin (CRYGS, P22914). CRYAB binds more strongly to the variant via a well-defined interaction surface. Reason: Protein binding is uninformative. This interaction reflects CRYAB's chaperone function in the lens -- it preferentially binds destabilized crystallin variants. This is better captured by the chaperone/holdase MF annotations. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:25910212, a large-scale study of macromolecular interaction perturbations in human genetic disorders. The WITH/FROM is CRYAA (P02489). Reason: Protein binding is uninformative. Large-scale interaction studies do not provide functional specificity beyond what is already captured by more specific annotations. |
| GO:0005515 protein binding | IPI PMID:26465331 Characterization of the Cardiac Overexpression of HSPB2 Reve... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:26465331 (Grose et al. 2015), which characterized the cardiac HSPB2 interactome. The WITH/FROM is HSPB2 (Q16082). CRYAB interacts with HSPB2, consistent with sHSP hetero-oligomerization. Reason: Protein binding is uninformative. The CRYAB-HSPB2 interaction is part of the sHSP oligomeric network and is better captured by more specific annotations. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:28514442, a large-scale interactome mapping study. The WITH/FROM is HSPB1 (P04792). Reason: Protein binding is uninformative. Large-scale interactome studies confirm known sHSP interactions but do not add functional specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:32296183, a reference map of the human binary protein interactome. The WITH/FROM includes CRYAA (P02489), KRTAP6-1 (Q3LI64), and GORASP2 (Q9H8Y8). Reason: Protein binding is uninformative. Large-scale binary interactome studies do not provide functional specificity. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:32814053, an interactome mapping study focused on neurodegenerative disease proteins. The WITH/FROM includes multiple proteins (APP/P05067, CTNNB1/P35222, EXOC5/O00471, ANXA4/P09525, PRPS1/P60891, CRMP1/Q14194, CORO6/Q6QEF8, ADAMTSL4/Q6UY14, PRUNE2/Q8WUY3, HSFY2/Q96LI6). Reason: Protein binding is uninformative. This large-scale interactome study identifies many interactors but the term does not capture the functional significance of any of these interactions. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:33961781, a dual proteome-scale network study. The WITH/FROM is HSPB1 (P04792). Reason: Protein binding is uninformative. Confirms CRYAB-HSPB1 interaction from large-scale proteomics. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:40205054, multimodal cell maps study. The WITH/FROM is HSPB1 (P04792). Reason: Protein binding is uninformative per GO curation guidelines. |
| GO:0042802 identical protein binding | IPI PMID:12601044 Alteration of protein-protein interactions of congenital cat... | ACCEPT | Summary: IPI annotation for identical protein binding (CRYAB self-interaction) from PMID:12601044 (Fu & Liang 2003). The study used mammalian two-hybrid to show CRYAB-CRYAB interaction, and that the R120G mutation decreases self-interaction. CRYAB forms large homo-oligomeric complexes. Reason: CRYAB self-association to form large homo-oligomeric complexes (typically 24-32 subunits) is a core feature of its biology. This is confirmed by multiple structural studies. The identical protein binding annotation is appropriate and more informative than generic protein binding. Supporting Evidence: PMID:12601044 for the R120G alphaB-crystallin, the interactions with alphaA- and alphaB-crystallin decreased, but those with betaB2- and gammaC-crystallin increased slightly. |
| GO:0042802 identical protein binding | IPI PMID:18330356 Construction and characterization of a normalized yeast two-... | ACCEPT | Summary: IPI annotation for identical protein binding from PMID:18330356 (normalized yeast two-hybrid library). Confirms CRYAB self-interaction. Reason: Confirms CRYAB homo-oligomerization by an independent method. Core property of CRYAB. |
| GO:0042802 identical protein binding | IPI PMID:19651604 The eye lens chaperone alpha-crystallin forms defined globul... | ACCEPT | Summary: IPI annotation from PMID:19651604 (Peschek et al. 2009), which demonstrated that alpha-crystallin forms defined globular assemblies. CRYAB self-interaction is central to its oligomeric architecture. Reason: CRYAB homo-oligomerization is a core structural property documented by multiple biophysical approaches. |
| GO:0042802 identical protein binding | IPI PMID:20802487 Solid-state NMR and SAXS studies provide a structural basis ... | ACCEPT | Summary: IPI annotation from PMID:20802487, which used solid-state NMR and SAXS to study CRYAB oligomer activation. Self-interaction confirmed by structural methods. Reason: Confirms CRYAB self-association by biophysical methods. Core property. |
| GO:0042802 identical protein binding | IPI PMID:21464278 N-terminal domain of alphaB-crystallin provides a conformati... | ACCEPT | Summary: IPI annotation from PMID:21464278, which showed that the N-terminal domain of CRYAB provides a conformational switch for multimerization and structural heterogeneity. Reason: Confirms CRYAB homo-oligomeric assembly, specifically identifying the N-terminal domain role. Core property. |
| GO:0042802 identical protein binding | IPI PMID:22143763 Multiple molecular architectures of the eye lens chaperone Ξ±... | ACCEPT | Summary: IPI annotation from PMID:22143763, which elucidated multiple molecular architectures of CRYAB oligomers using a triple hybrid approach. Reason: Confirms CRYAB polydisperse homo-oligomeric assembly by multiple structural methods. |
| GO:0042802 identical protein binding | IPI PMID:22153508 The polydispersity of Ξ±B-crystallin is rationalized by an in... | ACCEPT | Summary: IPI annotation from PMID:22153508 (Baldwin et al. 2011), which demonstrated the interconverting polyhedral architecture of CRYAB oligomers using NMR, mass spectrometry, and electron microscopy. Reason: Provides structural basis for CRYAB polydisperse oligomeric assembly. Core property. Supporting Evidence: PMID:22153508 We report structural models for the most abundant oligomers populated by the polydisperse molecular chaperone alphaB-crystallin. |
| GO:0042802 identical protein binding | IPI PMID:23188086 Binding determinants of the small heat shock protein, Ξ±B-cry... | ACCEPT | Summary: IPI annotation from PMID:23188086 (Delbecq et al. 2012), which characterized the IxI motif binding to the alpha-crystallin domain groove. This inter-subunit interaction is critical for oligomer formation. Reason: The IxI motif interaction is a key determinant of sHSP oligomer assembly and client binding. This study provides molecular detail on CRYAB self-interaction. Core property. Supporting Evidence: PMID:23188086 The most commonly observed inter-subunit interaction involves a highly conserved C-terminal 'IxI/V' motif and a groove in the ACD that is also implicated in client binding. |
| GO:0042802 identical protein binding | IPI PMID:24183572 Preferential and specific binding of human Ξ±B-crystallin to ... | ACCEPT | Summary: IPI annotation from PMID:24183572 (Kingsley et al. 2013). The WITH/FROM is CRYAB itself (P02511), reflecting self-interaction in the context of studying CRYAB binding to gammaS-crystallin variants. Reason: Confirms CRYAB self-interaction. Core property. |
| GO:0042802 identical protein binding | IPI PMID:26465331 Characterization of the Cardiac Overexpression of HSPB2 Reve... | ACCEPT | Summary: IPI annotation from PMID:26465331 (Grose et al. 2015), cardiac HSPB2 interactome study. The WITH/FROM is CRYAB itself (P02511). Reason: Confirms CRYAB self-interaction in cardiac context. |
| GO:0042802 identical protein binding | IPI PMID:27226619 The Human 343delT HSPB5 Chaperone Associated with Early-onse... | ACCEPT | Summary: IPI annotation from PMID:27226619, which studied the 343delT HSPB5 mutation associated with early-onset skeletal myopathy and its defects in protein solubility. Confirms CRYAB self-interaction. Reason: Confirms CRYAB self-interaction. Disease mutations affect oligomeric assembly, underscoring the functional importance of self-interaction. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer, based on mouse CRYAB (P23927). CRYAB has been reported to translocate to mitochondria in some contexts, particularly related to its anti-apoptotic function (sequestering Bax and Bcl-X(S) to prevent mitochondrial translocation, PMID:14752512). The anti-apoptotic mechanism involves preventing Bax translocation TO mitochondria rather than CRYAB being a mitochondrial resident protein. Reason: Mitochondrial localization may occur transiently or in specific contexts (e.g., during apoptosis regulation), but CRYAB is not a constitutive mitochondrial protein. The annotation from Ensembl Compara mouse ortholog transfer is acceptable but represents a non-core, context-dependent localization. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer for cytosol. CRYAB is primarily a cytosolic protein, supported by IDA evidence from GO_REF:0000052 (HPA immunofluorescence). Cytosol is consistent with the cytoplasm annotations. Reason: Cytosol is the more specific subcellular compartment within cytoplasm where CRYAB resides. Supported by IDA from HPA data and consistent with CRYAB's known biology as a soluble cytoplasmic chaperone. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for plasma membrane. Also supported by IDA from HPA immunofluorescence (GO_REF:0000052). CRYAB has been reported at the plasma membrane in some contexts (e.g., association with cadherin/catenin complexes at the cell membrane, PMID:22158051). Reason: Plasma membrane localization may occur in specific contexts (e.g., cell adhesion junctions) but is not a core localization of CRYAB. The HPA IDA data and mouse ortholog transfer provide some support, but cytoplasm/cytosol are the primary locations. |
| GO:0006457 protein folding | IEA GO_REF:0000107 | MODIFY | Summary: IEA annotation from Ensembl Compara ortholog transfer (from rat) for protein folding. CRYAB is a holdase chaperone that prevents protein aggregation but does NOT actively fold proteins. It keeps substrates in a folding-competent state that can then be refolded by ATP-dependent foldase chaperones like HSP70. The term protein folding implies direct participation in the folding process, which is misleading for a holdase. Reason: CRYAB is a holdase chaperone, not a foldase. It prevents aggregation and maintains substrates in a folding-competent state (PMID:19464326, PMID:16303126) but does not perform protein folding per se. GO:0050821 protein stabilization is more appropriate as a BP term. The annotation should be modified to reflect holdase activity rather than folding activity. Proposed replacements: protein stabilization Supporting Evidence: PMID:19464326 HSPB1 and HSPB5, that chaperoned heat unfolded substrates and kept them folding competent, HSPB7 did not support refolding. |
| GO:0008017 microtubule binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer (from rat CRYAB) for microtubule binding. There is limited direct evidence for CRYAB binding microtubules in human. CRYAB is better known for binding intermediate filaments (desmin) and actin filaments. The rat data may reflect CRYAB's broader cytoskeletal interactions. Reason: Microtubule binding is plausible given CRYAB's known interactions with cytoskeletal elements (desmin intermediate filaments, actin), but the primary cytoskeletal interaction is with intermediate filaments (PMID:28470624). The broader cytoskeletal protein binding annotation (GO:0008092) is also present and may be more appropriate. This is a non-core function. |
| GO:0008092 cytoskeletal protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer for cytoskeletal protein binding. CRYAB interacts with desmin intermediate filaments (PMID:28470624), titin (PMID:14676215), and associates with the sarcomeric cytoskeleton. This is well-supported. Reason: CRYAB has well-documented interactions with cytoskeletal proteins including desmin (PMID:28470624) and titin (UniProt, PMID:14676215). Mutations in CRYAB cause desmin-related myopathy (PMID:9731540), underscoring the functional importance of this interaction. The IEA annotation is appropriate. Supporting Evidence: PMID:28470624 the binding of CRYAB to desmin is subject to its assembly status, to the subunit organization within filaments formed and to the integrity of the C-terminal tail domain of desmin. |
| GO:0009986 cell surface | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for cell surface. CRYAB is primarily an intracellular protein. Some evidence suggests it can be secreted (PMID:32272059) and found in exosomes, but cell surface localization is not well-established for human CRYAB. Reason: Cell surface localization is not well-documented for human CRYAB. It may be transiently present at the cell surface during unconventional secretion. This is a non-core, context-dependent localization transferred from rat ortholog. |
| GO:0030018 Z disc | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer for Z disc localization. UniProt notes that CRYAB localizes at Z-bands and the intercalated disk in cardiomyocytes (PMID:28493373). This is consistent with its role in muscle and its interaction with desmin and titin. Reason: Z disc localization is documented for human CRYAB in cardiomyocytes (PMID:28493373) and is consistent with its interaction with sarcomeric proteins desmin and titin. This is a core localization in muscle tissue. |
| GO:0030308 negative regulation of cell growth | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for negative regulation of cell growth. CRYAB has been implicated in tumor suppression in some contexts (PMID:22158051 in NPC) and its overexpression can suppress tumor formation. However, this is not a core function. Reason: Negative regulation of cell growth is a secondary function of CRYAB, observed in certain cancer contexts (PMID:22158051). It is not a core function and likely reflects downstream consequences of its anti-apoptotic and chaperone activities rather than a direct growth regulatory function. |
| GO:0030424 axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for axon localization. CRYAB is expressed in the nervous system and accumulates in Alexander's disease brain. Axonal localization is plausible but represents a tissue-specific localization rather than core biology. Reason: Axon localization is transferred from rat ortholog. CRYAB is expressed in neural tissues and accumulates in neurological disease contexts, but axonal localization is not a core feature. Non-core tissue-specific localization. |
| GO:0031109 microtubule polymerization or depolymerization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA annotation from Ensembl Compara ortholog transfer for microtubule polymerization or depolymerization. There is limited direct evidence for CRYAB regulating microtubule dynamics in human. This may be an over-annotation from the rat ortholog. Reason: There is insufficient evidence that CRYAB directly regulates microtubule polymerization or depolymerization in human. CRYAB's primary cytoskeletal interactions are with intermediate filaments (desmin) rather than microtubules. This annotation likely represents an over-annotation from ortholog transfer. |
| GO:0031430 M band | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for M band localization. CRYAB interacts with titin, which spans from Z disc to M band. M band localization is plausible in the context of sarcomeric association. Reason: M band localization is consistent with CRYAB's interaction with titin and its sarcomeric association. However, the primary sarcomeric localization documented for human CRYAB is at Z-bands (PMID:28493373). M band is a secondary localization from rat ortholog transfer. |
| GO:0031674 I band | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for I band localization. I band localization is consistent with CRYAB's association with sarcomeric structures and its interaction with titin (which spans the I band). Reason: I band localization is plausible given CRYAB's interaction with titin and sarcomeric structures, but is transferred from rat ortholog. Non-core but reasonable for muscle tissue context. |
| GO:0032355 response to estradiol | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for response to estradiol. CRYAB expression may be regulated by estradiol in certain tissues, but this is not a core function. Reason: Response to estradiol is a secondary, context-dependent process for CRYAB. Many stress-responsive genes show altered expression in response to various stimuli including hormones. This is not a core function and is transferred from rat ortholog. |
| GO:0032432 actin filament bundle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for actin filament bundle localization. CRYAB has been reported to associate with actin cytoskeletal structures in addition to its well-known intermediate filament interactions. Reason: Actin filament bundle localization is a secondary cytoskeletal association for CRYAB. Its primary cytoskeletal interaction is with desmin intermediate filaments. Transferred from rat ortholog. |
| GO:0042542 response to hydrogen peroxide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for response to hydrogen peroxide. As a stress-responsive chaperone, CRYAB is likely upregulated during oxidative stress including H2O2 exposure. UniProt notes susceptibility to oxidation at Met-48, Met-60, and Trp-68. Reason: Response to hydrogen peroxide is consistent with CRYAB's role as a stress-responsive chaperone. It is a non-core, general stress response function rather than a specific core activity. Transferred from rat ortholog. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from combined automated methods for negative regulation of apoptotic process. This duplicates the IBA annotation and is also supported by IDA evidence from PMID:14752512. CRYAB's anti-apoptotic activity through binding Bax and Bcl-X(S) is well-established. Reason: This IEA annotation is consistent with the IBA and IDA evidence for CRYAB's anti-apoptotic function. PMID:14752512 provides direct experimental evidence. |
| GO:0043197 dendritic spine | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for dendritic spine localization. CRYAB is expressed in the nervous system and has been found in neural structures. Dendritic spine localization is plausible but represents a tissue-specific neural localization. Reason: Dendritic spine localization is a neural tissue-specific localization transferred from rat ortholog. CRYAB is expressed in the brain and accumulates in neurological disease contexts. Non-core, tissue-specific. |
| GO:0043204 perikaryon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for perikaryon (cell body of neuron) localization. CRYAB is expressed in neural tissues. Reason: Perikaryon localization is a neural tissue-specific localization transferred from rat ortholog. Non-core. |
| GO:0043292 contractile muscle fiber | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer for contractile muscle fiber localization. CRYAB is highly expressed in cardiac and skeletal muscle (HPA: tissue enhanced in heart muscle, skeletal muscle, tongue) and associates with sarcomeric structures. Reason: CRYAB is highly expressed in muscle tissue and localizes to sarcomeric structures (Z-bands, intercalated disks) as documented by PMID:28493373. Contractile muscle fiber localization is consistent with CRYAB's role in muscle and its association with desmin and titin. |
| GO:0051403 stress-activated MAPK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for stress-activated MAPK cascade. CRYAB has been reported to modulate MAPK signaling in some stress contexts, but this is not a core function. Reason: Stress-activated MAPK cascade involvement is a secondary consequence of CRYAB's stress-protective functions rather than a direct core activity. Transferred from rat ortholog. Non-core. |
| GO:0097060 synaptic membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for synaptic membrane localization. CRYAB is expressed in neural tissues. Synaptic membrane localization is a tissue-specific neural localization. Reason: Synaptic membrane localization is a neural tissue-specific localization transferred from rat ortholog. Non-core. |
| GO:0097512 cardiac myofibril | IEA GO_REF:0000107 | ACCEPT | Summary: IEA annotation from Ensembl Compara ortholog transfer for cardiac myofibril localization. CRYAB is highly expressed in cardiac muscle and localizes to sarcomeric structures including Z-bands and intercalated disks (PMID:28493373). Reason: Cardiac myofibril localization is well-supported by CRYAB's high expression in cardiac muscle (HPA, UniProt) and its documented localization at Z-bands and intercalated disks (PMID:28493373). CRYAB mutations cause cardiomyopathies, underscoring its cardiac muscle function. |
| GO:2000378 negative regulation of reactive oxygen species metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA annotation from Ensembl Compara ortholog transfer for negative regulation of reactive oxygen species metabolic process. CRYAB has been implicated in oxidative stress protection, but this is a secondary function. Reason: Negative regulation of ROS is a downstream protective effect of CRYAB's chaperone activity rather than a direct core function. Transferred from rat ortholog. Non-core. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation from HPA immunofluorescence curation for cytosol localization. CRYAB is a soluble cytoplasmic chaperone that resides in the cytosol under normal conditions. Reason: Cytosol localization is the primary subcellular localization of CRYAB under normal conditions. Supported by HPA immunofluorescence data and consistent with its role as a soluble chaperone. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: IDA annotation from HPA immunofluorescence curation for plasma membrane. Some plasma membrane signal may be detected by immunofluorescence but CRYAB is primarily cytosolic. Reason: Plasma membrane localization from HPA immunofluorescence is a secondary localization. CRYAB may associate with membrane-proximal structures in some contexts (e.g., cadherin/catenin complexes, PMID:22158051) but is primarily a cytosolic protein. Non-core. |
| GO:0043067 regulation of programmed cell death | IMP PMID:23542032 Protective role of the endoplasmic reticulum protein mitsugu... | ACCEPT | Summary: IMP annotation from PMID:23542032 (Yamashita et al. 2013) for regulation of programmed cell death. The study showed that knockdown of CRYAB facilitates death of UVC-exposed cells, and that CRYAB expressed as an ER-anchored form lowered UVC sensitivity. CRYAB binding to MG23/TMEM109 mediates protection against UVC-induced cell death. Reason: CRYAB's role in regulating programmed cell death is well-established. This annotation from PMID:23542032 specifically documents the protective role against UVC-induced cell death via interaction with TMEM109. This is consistent with CRYAB's broader anti-apoptotic function (PMID:14752512). The parent term regulation of programmed cell death is appropriate here since the paper demonstrates both protection and sensitization depending on CRYAB expression levels. Supporting Evidence: PMID:23542032 The small heat shock protein Ξ±B-crystallin (Ξ±BC) is identified as a MG23 binding molecule and its knockdown facilitates death of UVC-exposed cells. |
| GO:0005198 structural molecule activity | IDA PMID:16303126 Lenticular chaperones suppress the aggregation of the catara... | MODIFY | Summary: IDA annotation for structural molecule activity from PMID:16303126 (Pigaga & Quinlan 2006). This paper primarily demonstrates chaperone-like activity of alpha-crystallins in suppressing aggregation of T5P gamma C-crystallin. The structural molecule activity annotation may reflect CRYAB's dual role in the lens as both a structural protein and a chaperone. Reason: PMID:16303126 supports CRYAB/alpha-crystallin suppression of aggregation of the cataract-causing T5P gamma C-crystallin, which is chaperone/holdase activity rather than generic structural molecule activity. The true lens structural role is already captured more precisely by GO:0005212 "structural constituent of eye lens." Proposed replacements: unfolded protein carrier activity Supporting Evidence: PMID:16303126 These data therefore suggest a dual role for these chaperones in maintaining transparency in the lens. |
| GO:0032991 protein-containing complex | IDA PMID:16303126 Lenticular chaperones suppress the aggregation of the catara... | ACCEPT | Summary: IDA annotation for protein-containing complex from PMID:16303126. CRYAB forms large oligomeric complexes, typically of 24-32 subunits. This is a fundamental feature of its biology as a small heat shock protein. Reason: CRYAB forms large polydisperse homo-oligomeric and hetero-oligomeric complexes. This is a core structural feature well-documented by multiple biophysical studies (PMID:16303126, PMID:22153508, PMID:19651604). |
| GO:0042802 identical protein binding | IPI PMID:16303126 Lenticular chaperones suppress the aggregation of the catara... | ACCEPT | Summary: IPI annotation for identical protein binding from PMID:16303126, reflecting CRYAB self-association in the context of alpha-crystallin oligomeric complexes. Reason: Confirms CRYAB self-interaction, which is central to its oligomeric assembly. Core property. |
| GO:0031333 negative regulation of protein-containing complex assembly | IDA PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: IDA annotation from PMID:23106396 (Narayan et al. 2012) for negative regulation of protein-containing complex assembly. The study demonstrated that CRYAB binds to misfolded amyloid-beta oligomeric species, forming long-lived complexes that prevent further growth into fibrils and prevent their dissociation. This is a manifestation of CRYAB's holdase chaperone activity applied to amyloid aggregation. Reason: This annotation captures an important aspect of CRYAB's chaperone function -- it prevents further assembly of amyloid-beta oligomers into fibrils. PMID:23106396 provides direct experimental evidence using single-molecule fluorescence techniques. Supporting Evidence: PMID:23106396 both chaperones bind to misfolded oligomeric species and form long-lived complexes, thereby preventing both their further growth into fibrils and their dissociation. |
| GO:0005515 protein binding | IPI PMID:20587334 Synergistic efficacy of LBH and alphaB-crystallin through in... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:20587334 (Deng et al. 2010), which identified LBH (Q53QV2) as a CRYAB-interacting partner by yeast two-hybrid and confirmed by co-immunoprecipitation and GST pull-down. The interaction leads to synergistic repression of p53 and p21 transcriptional activities. Reason: Protein binding is uninformative. The CRYAB-LBH interaction is interesting but the term does not capture the functional significance. The downstream functional consequence is captured by the negative regulation of DNA-templated transcription annotation from the same paper. |
| GO:0005634 nucleus | IDA PMID:20587334 Synergistic efficacy of LBH and alphaB-crystallin through in... | ACCEPT | Summary: IDA annotation for nucleus localization from PMID:20587334. The study showed that CRYAB, which is normally cytoplasmic, accumulates partially in the nucleus when co-transfected with LBH in COS-7 cells. Reason: Nuclear localization of CRYAB is confirmed by direct observation in PMID:20587334, consistent with other IDA evidence from PMID:19464326. CRYAB translocates to the nucleus under specific conditions. Supporting Evidence: PMID:20587334 alphaB-crystallin that is cytoplasmic alone, accumulates partialy in the nucleus when co-transfected with LBH. |
| GO:0005737 cytoplasm | IDA PMID:20587334 Synergistic efficacy of LBH and alphaB-crystallin through in... | ACCEPT | Summary: IDA annotation for cytoplasm localization from PMID:20587334. CRYAB is cytoplasmic when expressed alone in COS-7 cells. Reason: Cytoplasm is the primary localization of CRYAB, confirmed by direct observation in PMID:20587334. |
| GO:0032991 protein-containing complex | IDA PMID:20587334 Synergistic efficacy of LBH and alphaB-crystallin through in... | ACCEPT | Summary: IDA annotation for protein-containing complex from PMID:20587334. CRYAB forms a complex with LBH as shown by co-immunoprecipitation and GST pull-down. Reason: CRYAB forms complexes with multiple partners. The complex with LBH is documented by co-immunoprecipitation in PMID:20587334. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:20587334 Synergistic efficacy of LBH and alphaB-crystallin through in... | KEEP AS NON CORE | Summary: IDA annotation from PMID:20587334 for negative regulation of DNA-templated transcription. Overexpression of CRYAB reduced the transcriptional activities of p53 and p21 promoters, and co-expression with LBH resulted in stronger repression. This is a secondary/non-core function of CRYAB. Reason: While the experimental evidence from PMID:20587334 supports that CRYAB can repress transcription from p53 and p21 promoters, this is likely a secondary consequence of CRYAB's interaction with LBH and its general protein-binding chaperone activity rather than a core transcriptional regulatory function. CRYAB is not a transcription factor. This function is non-core. Supporting Evidence: PMID:20587334 Transient transfection assays indicated that overexpression of LBH or alphaB-crystallin reduced the transcriptional activities of p53 and p21, respectively, Overexpression of both alphaB-crystallin and LBH together resulted in a stronger repression of the transcriptional activities of p21 and p53. |
| GO:0001540 amyloid-beta binding | IPI PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: IPI annotation from PMID:23106396 (Narayan et al. 2012) for amyloid-beta binding. Using single-molecule fluorescence techniques, the study demonstrated that CRYAB binds to amyloid-beta oligomeric species, forming long-lived complexes. The WITH/FROM is APP processed to amyloid-beta (P05067-PRO_0000000093). Reason: CRYAB binding to amyloid-beta oligomers is well-documented (PMID:23106396, PMID:17046756). This is a specific manifestation of CRYAB's holdase chaperone activity -- it sequesters misfolded amyloid-beta species. CRYAB is found co-localized with amyloid-beta in senile plaques of Alzheimer's disease patients. This is a meaningful specific MF annotation. Supporting Evidence: PMID:23106396 both chaperones bind to misfolded oligomeric species and form long-lived complexes, thereby preventing both their further growth into fibrils and their dissociation. PMID:17046756 Interactions between Abeta and alphaB-crystallin involve the hydrophobic core residues 17-21 as well as residues 31-32 of Abeta, and thus the same chemical groups which are important for Abeta aggregation. |
| GO:0044877 protein-containing complex binding | IPI PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: IPI annotation from PMID:23106396 for protein-containing complex binding. The WITH/FROM is ComplexPortal:CPX-1180, which refers to the amyloid-beta oligomeric complex. CRYAB binds to these oligomeric complexes as shown by single-molecule fluorescence. Reason: CRYAB binds to amyloid-beta oligomeric complexes (PMID:23106396). This annotation specifically captures the binding to a protein-containing complex (the amyloid-beta oligomer) as opposed to individual amyloid-beta monomers. This reflects CRYAB's holdase function of sequestering aggregation-prone complexes. |
| GO:0005515 protein binding | IPI PMID:28470624 Ξ±B-crystallin is a sensor for assembly intermediates and for... | MODIFY | Summary: IPI annotation from PMID:28470624 (Sharma et al. 2017), which showed CRYAB is a sensor for assembly intermediates and subunit topology of desmin intermediate filaments. The WITH/FROM is desmin (DES, P17661). CRYAB binds rapidly during early stages of desmin filament assembly. Reason: Protein binding is uninformative. The CRYAB-desmin interaction is a functionally significant interaction that reflects CRYAB's role as a chaperone for cytoskeletal assembly. This should be annotated as cytoskeletal protein binding (GO:0008092) which is already present as an IEA annotation, providing experimental support for that more specific term. Proposed replacements: cytoskeletal protein binding Supporting Evidence: PMID:28470624 the binding of CRYAB to desmin is subject to its assembly status, to the subunit organization within filaments formed and to the integrity of the C-terminal tail domain of desmin. |
| GO:1905907 negative regulation of amyloid fibril formation | IDA PMID:23106396 Amyloid-Ξ² oligomers are sequestered by both intracellular an... | ACCEPT | Summary: IDA annotation from PMID:23106396 for negative regulation of amyloid fibril formation. CRYAB sequesters amyloid-beta oligomers, preventing their further growth into fibrils. This is a specific application of CRYAB's holdase chaperone function to amyloid aggregation. Reason: PMID:23106396 directly demonstrates that CRYAB prevents amyloid-beta oligomers from growing into fibrils using single-molecule fluorescence techniques. This is a well-supported annotation that captures a specific biological consequence of CRYAB's holdase activity. Supporting Evidence: PMID:23106396 both chaperones bind to misfolded oligomeric species and form long-lived complexes, thereby preventing both their further growth into fibrils and their dissociation. |
| GO:0005515 protein binding | IPI PMID:12235146 Role of the C-terminal extensions of alpha-crystallins. Swap... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:12235146 (Pasta et al. 2002), which studied C-terminal extension swapping between alphaA- and alphaB-crystallins. The WITH/FROM includes aldolase (P00883) and rhodanese (P11415), which are substrate proteins used in chaperone activity assays. CRYAB binding to these substrates reflects its holdase chaperone activity. Reason: Protein binding is uninformative. The interactions with aldolase and rhodanese are chaperone-substrate interactions used as in vitro assay substrates. This is better captured by the chaperone function annotations (GO:0140309 or GO:0050821). |
| GO:0050821 protein stabilization | IMP PMID:12235146 Role of the C-terminal extensions of alpha-crystallins. Swap... | ACCEPT | Summary: IMP annotation from PMID:12235146 (Pasta et al. 2002) for protein stabilization. The study demonstrated that CRYAB (and chimeric variants) prevent aggregation of various substrate proteins (thermal and non-thermal models), demonstrating chaperone-like activity. The C-terminal extension plays a crucial role in structure and chaperone activity. Reason: Protein stabilization is an excellent BP term for CRYAB's holdase chaperone activity. CRYAB prevents aggregation of denatured proteins and maintains them in a soluble, folding-competent state. This is a core function of CRYAB. PMID:12235146 provides direct evidence for chaperone-like activity using multiple protein substrates. Supporting Evidence: PMID:12235146 We have used thermal and non-thermal models of protein aggregation and found that the chimeric alphaB with the C-terminal extension of alphaA-crystallin, alphaBAc, exhibits dramatically enhanced chaperone-like activity. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5082356 | ACCEPT | Summary: TAS annotation from Reactome pathway R-HSA-5082356 (HSF1-mediated gene expression) for nucleoplasm localization. CRYAB translocates to the nucleus during heat stress (PMID:19464326) and specifically resides in SC35 speckles within the nucleoplasm. Reason: Nucleoplasm localization is consistent with CRYAB's documented nuclear translocation during heat stress (PMID:19464326). SC35 speckles are nucleoplasmic structures. The Reactome annotation for HSF1-mediated gene expression context is appropriate. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | ACCEPT | Summary: HDA annotation from PMID:23533145, an in-depth proteomic study of exosomes isolated from expressed prostatic secretions in urine. CRYAB was identified in exosome fractions by mass spectrometry. Reason: CRYAB has been identified in extracellular exosomes by proteomic studies (PMID:23533145). This is consistent with the unconventional secretion pathway described in PMID:32272059. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | ACCEPT | Summary: HDA annotation from PMID:19056867, a large-scale proteomics and phosphoproteomics study of urinary exosomes. CRYAB was identified in exosome fractions. Reason: Independent confirmation of CRYAB in extracellular exosomes by urinary exosome proteomics. |
| GO:0071480 cellular response to gamma radiation | IMP PMID:23542032 Protective role of the endoplasmic reticulum protein mitsugu... | MODIFY | Summary: IMP annotation from PMID:23542032 for cellular response to gamma radiation. The paper actually studies UVC-induced cell death, not gamma radiation specifically. It shows CRYAB knockdown facilitates death of UVC-exposed cells. This annotation may reflect broader DNA damage response involvement. Reason: PMID:23542032 specifically demonstrates CRYAB's protective role against UVC-induced cell death, not gamma radiation. The correct response term for this evidence is cellular response to UV-C, and CRYAB's role in DNA damage response is secondary to its core chaperone and anti-apoptotic functions. Proposed replacements: cellular response to UV-C Supporting Evidence: PMID:23542032 knockdown of the ER protein mitsugumin23 (MG23) enhances cell death induced by ultraviolet C (UVC), which causes DNA damage. |
| GO:0005515 protein binding | IPI PMID:14752512 Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S... | MARK AS OVER ANNOTATED | Summary: IPI annotation from PMID:14752512 (Mao et al. 2004). The WITH/FROM includes Bax (Q07812) and Bcl-X(S) (Q07817). CRYAB binds pro-apoptotic Bax and Bcl-X(S) to sequester their translocation during apoptosis. Reason: Protein binding is uninformative. The functionally significant interaction with Bax and Bcl-X(S) is better captured by the negative regulation of apoptotic process annotations. The specific anti-apoptotic mechanism involves sequestering these pro-apoptotic factors in the cytoplasm. |
| GO:0005634 nucleus | IDA PMID:19464326 HSPB7 is a SC35 speckle resident small heat shock protein. | ACCEPT | Summary: IDA annotation from PMID:19464326 (Vos et al. 2009) for nucleus localization. The study used confocal microscopy to show CRYAB (HSPB5) translocates to the nucleus during heat shock, where it resides in SC35 speckles. This is a well-documented stress-dependent nuclear localization. Reason: Direct microscopy evidence for CRYAB nuclear translocation during heat stress. PMID:19464326 is the key study documenting stress-dependent nuclear localization and SC35 speckle residence for CRYAB. Supporting Evidence: PMID:19464326 Some members also show a dynamic, stress-induced translocation to SC35 splicing speckles. |
| GO:0005737 cytoplasm | IDA PMID:19464326 HSPB7 is a SC35 speckle resident small heat shock protein. | ACCEPT | Summary: IDA annotation from PMID:19464326 for cytoplasm localization. CRYAB localizes to the cytoplasm under normal (unstressed) conditions. Reason: Direct microscopy evidence for cytoplasmic localization under normal conditions (PMID:19464326). |
| GO:0005737 cytoplasm | IDA GO_REF:0000054 | ACCEPT | Summary: IDA annotation from GO_REF:0000054, based on curation of intracellular localizations of expressed fusion proteins in living cells (LIFEdb). Confirms cytoplasmic localization. Reason: Independent confirmation of cytoplasmic localization from expressed fusion protein imaging. |
| GO:0042803 protein homodimerization activity | IPI PMID:19646995 Crystal structures of alpha-crystallin domain dimers of alph... | ACCEPT | Summary: IPI annotation from PMID:19646995 (Bagneris et al. 2009) for protein homodimerization activity. The crystal structure of the alpha-crystallin domain dimer of CRYAB was solved at 2.63 angstroms, showing that the alpha- crystallin domain forms homodimers with a shared groove at the interface. The dimer is the basic building block for higher-order oligomeric assembly. Reason: The crystal structure of CRYAB alpha-crystallin domain homodimers (PMID:19646995) directly demonstrates protein homodimerization activity. The dimer is the fundamental building block of the CRYAB oligomeric assembly. This is a core structural property. Supporting Evidence: PMID:19646995 crystal structures of excised alpha-crystallin domain from rat Hsp20 and that from human alphaB-crystallin show that they form homodimers with a shared groove at the interface by extending a beta sheet. |
| GO:0051082 unfolded protein binding | IPI PMID:16303126 Lenticular chaperones suppress the aggregation of the catara... | MODIFY | Summary: GO:0051082 "unfolded protein binding" is now formally obsolete (go-ontology#30962). This IPI annotation is based on PMID:16303126, which demonstrated that alpha B-crystallin (CRYAB) suppresses the aggregation of the cataract-causing T5P mutant gamma C-crystallin. In this study, CRYAB increased the solubility of T5P gamma C-crystallin both in vitro (by sedimentation assay and sucrose gradient centrifugation) and in transfected cells, and significantly reduced the size of T5P gamma C-crystallin aggregates. The interacting partner (WITH/FROM) is the destabilized T5P gamma C-crystallin. The paper describes this as "chaperone-like activity" with a "dual role" -- increasing soluble protein fraction and reducing aggregate size. This is classic holdase activity: CRYAB binds partially denatured proteins and prevents their aggregation, but does NOT refold them. The term GO:0140309 "unfolded protein carrier activity" is the appropriate MF replacement term because CRYAB prevents aggregation without active refolding. Reason: GO:0051082 is now formally obsolete. The experimental evidence from PMID:16303126 clearly demonstrates holdase chaperone activity -- CRYAB suppresses aggregation of the destabilized T5P mutant gamma C-crystallin and increases its solubility. The paper explicitly describes "a dual role for these chaperones in maintaining transparency in the lens": increasing the proportion of soluble protein and reducing aggregate size. This is not passive "unfolded protein binding" but active suppression of aggregation (holdase function). The IPI evidence with T5P gamma C-crystallin as the interacting partner is strong. GO:0140309 "unfolded protein holdase activity" is the correct current MF term since CRYAB prevents aggregation but does NOT refold proteins. Proposed replacements: unfolded protein carrier activity Supporting Evidence: PMID:16303126 the major lenticular protein chaperones, alpha A- and alpha B-crystallin, increased the solubility of the T5P gamma C-crystallin both in vitro and in transfected cells. More importantly, the size of the T5P gamma C-crystallin aggregates were also significantly reduced in the presence of the lenticular chaperones. PMID:16303126 These data therefore suggest a dual role for these chaperones in maintaining transparency in the lens. The first is that these protein chaperones increase the proportion of the soluble T5P gamma C-crystallin and the second is that they also reduce light scatter by reducing the aggregate size of T5P gamma C-crystallin. |
| GO:0005737 cytoplasm | IDA PMID:14752512 Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S... | ACCEPT | Summary: IDA annotation from PMID:14752512 (Mao et al. 2004) for cytoplasm localization. The study demonstrated that CRYAB is cytoplasmic and prevents translocation of Bax and Bcl-X(S) from cytosol into mitochondria. Reason: Cytoplasmic localization confirmed by direct observation in PMID:14752512. The anti-apoptotic mechanism requires CRYAB to be cytoplasmic to sequester pro-apoptotic factors. Supporting Evidence: PMID:14752512 alpha-crystallins prevent the translocation of Bax and Bcl-X(S) from cytosol into mitochondria during staurosporine-induced apoptosis. |
| GO:0032387 negative regulation of intracellular transport | IDA PMID:14752512 Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S... | ACCEPT | Summary: IDA annotation from PMID:14752512 for negative regulation of intracellular transport. CRYAB prevents the translocation of Bax and Bcl-X(S) from the cytosol to mitochondria during staurosporine-induced apoptosis. This sequestration of pro-apoptotic factors is a specific form of negative regulation of intracellular transport. Reason: PMID:14752512 directly demonstrates that CRYAB prevents the cytosol-to-mitochondria translocation of Bax and Bcl-X(S). This is a specific anti-apoptotic mechanism involving negative regulation of intracellular protein transport. The annotation is well-supported by direct experimental evidence. Supporting Evidence: PMID:14752512 Through the interaction, alpha-crystallins prevent the translocation of Bax and Bcl-X(S) from cytosol into mitochondria during staurosporine-induced apoptosis. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:14752512 Human alphaA- and alphaB-crystallins bind to Bax and Bcl-X(S... | ACCEPT | Summary: IDA annotation from PMID:14752512 for negative regulation of apoptotic process. The study demonstrates a clear anti-apoptotic mechanism: CRYAB binds Bax and Bcl-X(S) to prevent their mitochondrial translocation, preserves mitochondrial integrity, restricts cytochrome c release, represses caspase-3 activation, and blocks PARP degradation. Reason: This is one of the strongest pieces of evidence for CRYAB's anti-apoptotic function. PMID:14752512 provides a complete mechanistic pathway from initial binding (Bax/Bcl-X(S) sequestration) to downstream consequences (preserved mitochondrial integrity, blocked caspase-3 activation). This is a core function of CRYAB. Supporting Evidence: PMID:14752512 alpha-crystallins preserve the integrity of mitochondria, restrict release of cytochrome c, repress activation of caspase-3 and block degradation of PARP. Thus, our results demonstrate a novel antiapoptotic mechanism for alpha-crystallins. |
| GO:0006457 protein folding | NAS PMID:9731540 A missense mutation in the alphaB-crystallin chaperone gene ... | MODIFY | Summary: NAS annotation from PMID:9731540 (Vicart et al. 1998) for protein folding. The paper identified the R120G mutation in CRYAB that causes desmin-related myopathy and describes CRYAB as possessing molecular chaperone activity. However, CRYAB is a holdase, not a foldase. It prevents aggregation but does not actively fold proteins. Reason: PMID:9731540 describes CRYAB as a molecular chaperone but does not demonstrate protein folding activity. CRYAB prevents protein aggregation (holdase activity) but does not refold denatured proteins. GO:0050821 protein stabilization is more appropriate. The NAS evidence code itself is weak (non-traceable author statement). Proposed replacements: protein stabilization Supporting Evidence: PMID:9731540 AlphaB-crystallin is a member of the small heat shock protein (shsp) family and possesses molecular chaperone activity. |
| GO:0006936 muscle contraction | TAS PMID:9731540 A missense mutation in the alphaB-crystallin chaperone gene ... | KEEP AS NON CORE | Summary: TAS annotation from PMID:9731540 for muscle contraction. The paper identified the CRYAB R120G mutation causing desmin-related myopathy. While CRYAB is important for muscle function (interacting with desmin and titin), it is not a direct participant in the muscle contraction machinery. Rather, it serves as a chaperone for muscle structural proteins. Reason: CRYAB is not directly involved in the muscle contraction mechanism. Its role in muscle is as a chaperone for cytoskeletal and sarcomeric proteins (desmin, titin). Loss of CRYAB function leads to myopathy through aggregation of desmin, not through direct contractile defects. The TAS evidence is weak, and the association with muscle contraction is indirect. Non-core. Supporting Evidence: PMID:9731540 We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family. |
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