CRYAB

Alpha-crystallin B chain is a protein that in humans is encoded by the CRYAB gene.[5] It is part of the small heat shock protein family and functions as molecular chaperone that primarily binds misfolded proteins to prevent protein aggregation, as well as inhibit apoptosis and contribute to intracellular architecture.[6][7][8] Post-translational modifications decrease the ability to chaperone.[6][8] Mutations in CRYAB cause different cardiomyopathies [9] and skeletal myopathies.[10] In addition, defects in this gene/protein have been associated with cancer and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.[6][7][8]

CRYAB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KLR, 2N0K, 2WJ7, 2Y1Y, 2Y1Z, 2Y22, 2YGD, 3L1G, 3SGM, 3SGN, 3SGO, 3SGP, 3SGR, 3SGS, 4M5S, 4M5T, 3J07
Identifiers
Aliases	CRYAB, CMD1II, CRYA2, CTPP2, CTRCT16, HEL-S-101, HSPB5, MFM2, crystallin alpha B
External IDs	OMIM: 123590 MGI: 88516 HomoloGene: 68209 GeneCards: CRYAB
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q23.1 Start 111,908,564 bp[1] End 111,923,722 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 A5.3|9 27.75 cM Start 50,751,325 bp[2] End 50,756,636 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein homodimerization activity • microtubule binding • unfolded protein binding • metal ion binding • cytoskeletal protein binding • GO:0001948 protein binding • structural constituent of eye lens • identical protein binding • amyloid-beta binding • GO:0032403 macromolecular complex binding Cellular component • cytoplasm • Golgi apparatus • I band • microtubule cytoskeleton • nucleoplasm • cell surface • actin filament bundle • extracellular exosome • cell nucleus • cardiac myofibril • perikaryon • dendritic spine • synaptic membrane • synapse • M band • GO:0097483, GO:0097481 postsynaptic density • axon • mitochondrion • cytosol • cell membrane • Z disc • contractile fiber • macromolecular complex Biological process • negative regulation of intracellular transport • response to estradiol • muscle contraction • regulation of cell death • aging • negative regulation of apoptotic process • microtubule polymerization or depolymerization • protein folding • stress-activated MAPK cascade • negative regulation of cell growth • cellular response to gamma radiation • regulation of cellular response to heat • negative regulation of reactive oxygen species metabolic process • protein homooligomerization • response to hydrogen peroxide • response to hypoxia • lens development in camera-type eye • tubulin complex assembly • muscle organ development • multicellular organism aging • negative regulation of gene expression • negative regulation of protein homooligomerization • camera-type eye development • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • protein stabilization • apoptotic process involved in morphogenesis • negative regulation of amyloid fibril formation • negative regulation of transcription, DNA-templated Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1410	12955
Ensembl	ENSG00000109846	ENSMUSG00000032060
UniProt	P02511	P23927
RefSeq (mRNA)	NM_001289807 NM_001289808 NM_001885 NM_001330379 NM_001368245 NM_001368246	NM_001289782 NM_001289784 NM_001289785 NM_009964
RefSeq (protein)	NP_001276736 NP_001276737 NP_001317308 NP_001876 NP_001355174 NP_001355175	NP_001276711 NP_001276713 NP_001276714 NP_034094
Location (UCSC)	Chr 11: 111.91 – 111.92 Mb	Chr 9: 50.75 – 50.76 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups.

Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. These heterogeneous aggregates consist of 30–40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively.[6]

Function

Alpha B chain crystallins (αBC) can be induced by heat shock, ischemia, and oxidation, and are members of the small heat shock protein (sHSP also known as the HSP20) family.[6][11] They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead, they bind improperly folded proteins to prevent protein aggregation.[6][7][8]

Furthermore, αBC may confer stress resistance to cells by inhibiting the processing of the pro-apoptotic protein caspase-3.[8] Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy.[6]

Clinical significance

Although not yet clearly understood, defective chaperone activity is expected to trigger the accumulation of protein aggregates and underlie the development of α-crystallinopathy, or the failure of protein quality control, resulting in protein deposition diseases such as Alzheimer’s disease and Parkinson’s disease. Mutations in CRYAB could also cause restrictive cardiomyopathy.[12] ER-anchored αBC can suppress aggregate formation mediated by the disease mutant. Thus, modulation of the micromilieu surrounding the ER membrane can serve as a potential target in developing pharmacological interventions for protein deposition disease.[7]

Though expressed highly in eye lens and muscle tissues, αBC can also be found in several types of cancer, among which head and neck squamous cell carcinoma (HNSCC) and breast carcinomas, as well as in patients with tuberous sclerosis.[13] αBC expression is associated with metastasis formation in HNSCC and in breast carcinomas and in other types of cancer, expression is often correlated with poor prognosis as well.[14] The expression of αBC can be increased during various stresses, like heat shock, osmotic stress or exposure to heavy metals, which then may lead to prolonged survival of cells under these conditions.[8]

Interactions

CRYAB has been shown to interact with:

• CRYAA,[15]
• CRYBB2,[15]
• CRYGC,[15]
• HSPB2,[16]
• Hsp27,[15][17] and
• PSMA3.[18]

See also

• Alpha crystallin

References

1. GRCh38: Ensembl release 89: ENSG00000109846 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032060 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Jeanpierre C, Austruy E, Delattre O, Jones C, Junien C (March 1993). "Subregional physical mapping of an alpha B-crystallin sequence and of a new expressed sequence D11S877E to human 11q". Mammalian Genome. 4 (2): 104–8. doi:10.1007/BF00290434. PMID 8431633.
6. "Entrez Gene: CRYAB crystallin, alpha B".
7. Yamamoto S, Yamashita A, Arakaki N, Nemoto H, Yamazaki T (December 2014). "Prevention of aberrant protein aggregation by anchoring the molecular chaperone αB-crystallin to the endoplasmic reticulum". Biochemical and Biophysical Research Communications. 455 (3–4): 241–5. doi:10.1016/j.bbrc.2014.10.151. PMID 25449278.
8. van de Schootbrugge C, Schults EM, Bussink J, Span PN, Grénman R, Pruijn GJ, Kaanders JH, Boelens WC (April 2014). "Effect of hypoxia on the expression of αB-crystallin in head and neck squamous cell carcinoma". BMC Cancer. 14: 252. doi:10.1186/1471-2407-14-252. PMC 3990244. PMID 24725344.
9. Brodehl, Andreas; Gaertner-Rommel, Anna; Klauke, Bärbel; Grewe, Simon Andre; Schirmer, Ilona; Peterschröder, Andreas; Faber, Lothar; Vorgerd, Matthias; Gummert, Jan (August 2017). "The novel αB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy". Human Mutation. 38 (8): 947–952. doi:10.1002/humu.23248. ISSN 1098-1004. PMID 28493373.
10. Vicart, P.; Caron, A.; Guicheney, P.; Li, Z.; Prévost, M. C.; Faure, A.; Chateau, D.; Chapon, F.; Tomé, F. (September 1998). "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy". Nature Genetics. 20 (1): 92–95. doi:10.1038/1765. ISSN 1061-4036. PMID 9731540.
11. Easterbrook M, Trope G (1989). "Value of Humphrey perimetry in the detection of early chloroquine retinopathy". Lens and Eye Toxicity Research. 6 (1–2): 255–68. PMID 2488020.
12. Brodehl A, Gaertner-Rommel A, Klauke B, Grewe SA, Schirmer I, Peterschröder A, Faber L, Vorgerd M, Gummert J, Anselmetti D, Schulz U, Paluszkiewicz L, Milting H (August 2017). "The novel αB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy". Human Mutation. 38 (8): 947–952. doi:10.1002/humu.23248. PMID 28493373.
13. Wang F, Chen X, Li C, Sun Q, Chen Y, Wang Y, Peng H, Liu Z, Chen R, Liu K, Yan H, Ye BH, Kwiatkowski DJ, Zhang H (August 2014). "Pivotal role of augmented αB-crystallin in tumor development induced by deficient TSC1/2 complex". Oncogene. 33 (34): 4352–8. doi:10.1038/onc.2013.401. PMID 24077282.
14. Moyano JV, Evans JR, Chen F, Lu M, Werner ME, Yehiely F, Diaz LK, Turbin D, Karaca G, Wiley E, Nielsen TO, Perou CM, Cryns VL (January 2006). "AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer". The Journal of Clinical Investigation. 116 (1): 261–70. doi:10.1172/JCI25888. PMC 1323258. PMID 16395408.
15. Fu L, Liang JJ (February 2002). "Detection of protein-protein interactions among lens crystallins in a mammalian two-hybrid system assay". The Journal of Biological Chemistry. 277 (6): 4255–60. doi:10.1074/jbc.M110027200. PMID 11700327.
16. Sugiyama Y, Suzuki A, Kishikawa M, Akutsu R, Hirose T, Waye MM, Tsui SK, Yoshida S, Ohno S (January 2000). "Muscle develops a specific form of small heat shock protein complex composed of MKBP/HSPB2 and HSPB3 during myogenic differentiation". The Journal of Biological Chemistry. 275 (2): 1095–104. doi:10.1074/jbc.275.2.1095. PMID 10625651.
17. Kato K, Shinohara H, Goto S, Inaguma Y, Morishita R, Asano T (April 1992). "Copurification of small heat shock protein with alpha B crystallin from human skeletal muscle". The Journal of Biological Chemistry. 267 (11): 7718–25. PMID 1560006.
18. Boelens WC, Croes Y, de Jong WW (January 2001). "Interaction between αB-crystallin and the human 20S proteasomal subunit C8/α7". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1544 (1–2): 311–9. doi:10.1016/S0167-4838(00)00243-0. PMID 11341940.

Further reading

• Derham BK, Harding JJ (July 1999). "Alpha-crystallin as a molecular chaperone". Progress in Retinal and Eye Research. 18 (4): 463–509. doi:10.1016/S1350-9462(98)00030-5. PMID 10217480.
• Calinisan V, Gravem D, Chen RP, Brittin S, Mohandas N, Lecomte MC, Gascard P (May 2006). "New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium". Frontiers in Bioscience. 11: 1646–66. doi:10.2741/1911. PMID 16368544.

External links

• GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy