Biology:CDK5RAP2
 Generic protein structure example |
CDK5 regulatory subunit-associated protein 2 is a protein that in humans is encoded by the CDK5RAP2 gene. It has necessary roles in the formation and stability of microtubules from the centrosome[1] and has been found to be linked to human brain size variation in males.[2] Multiple transcript variants exist for this gene, but the full-length nature of only two has been determined.[3][4]
CDK5RAP2 is homologous to the Drosophila protein centrosomin (cnn)[5] and paralogous to myomegalin, which in mammals contains an Olduvai domain, a domain implicated in human brain size evolution.[6][7]
Function
CDK5RAP2 is necessary for the proper formation, anchoring and orientation of microtubules from the centrosome. It binds with the γ-tubulin ring complex (γTuRC), and this is required for the γTuRC to attach to the centrosome.[1] CDK5RAP2 also binds to p25, a form of CDK5R1 that serves as the activating subunit of CDK5, which is involved in the regulation of neuronal differentiation. CDK5RAP2 therefore has a role in neuronal differentiation.[4] CDK5RAP2 is also necessary as a scaffolding protein in the centrosomal corona of Dictyostelium.[8]
Clinical significance
Human brain size variation
An MRI study has demonstrated a link between common human variation in the CDK5RAP2 gene and brain structure. More specifically, associations were found between several single nucleotide polymorphisms (SNPs) and brain cortical surface area and total brain volume. These associations were found exclusively in male subjects, and all SNPs were located either in the last 7 introns or downstream of the gene. The functional significance of these loci is not yet known. However, given their location close to regulatory elements, it is possible that they are involved in gene regulation, which suggests that common variance in brain structure could be associated with differences in gene regulation rather than protein structure, consistent with findings in other complex human traits.[2] CDK5RAP2 is a paralogue of myomegalin, which in mammals contains an Olduvai domain, a domain with human-specific duplications that have been implicated in human brain size evolution.[6][7]
Autosomal recessive primary microcephaly
Mutations in CDK5RAP2 cause autosomal recessive primary microcephaly type 3.[9][1]
Interactions
CDK5RAP2 has been shown to interact with CDK5R1[10] and pericentrin (PCTN).[4]
History
The gene was discovered in 2000[11] and was first characterised in 2007.[1]
References
- ↑ 1.0 1.1 1.2 1.3 "CDK5RAP2 is a pericentriolar protein that functions in centrosomal attachment of the gamma-tubulin ring complex". Molecular Biology of the Cell 19 (1): 115–25. January 2008. doi:10.1091/mbc.E07-04-0371. PMID 17959831.
- ↑ 2.0 2.1 "Sex-dependent association of common variants of microcephaly genes with brain structure". Proceedings of the National Academy of Sciences of the United States of America 107 (1): 384–8. January 2010. doi:10.1073/pnas.0908454107. PMID 20080800. Bibcode: 2010PNAS..107..384R.
- ↑ "Cloning of three novel neuronal Cdk5 activator binding proteins". Gene 242 (1–2): 285–94. January 2000. doi:10.1016/S0378-1119(99)00499-0. PMID 10721722.
- ↑ 4.0 4.1 4.2 "Entrez Gene: CDK5RAP2 CDK5 regulatory subunit associated protein 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55755.
- ↑ "CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response". The Journal of Cell Biology 189 (1): 23–39. April 2010. doi:10.1083/jcb.200912163. PMID 20368616.
- ↑ 6.0 6.1 "Gene copy number variation spanning 60 million years of human and primate evolution". Genome Research 17 (9): 1266–77. September 2007. doi:10.1101/gr.6557307. PMID 17666543.
- ↑ 7.0 7.1 "Evolutionary history and genome organization of DUF1220 protein domains". G3 2 (9): 977–86. September 2012. doi:10.1534/g3.112.003061. PMID 22973535.
- ↑ "CDK5RAP2 Is an Essential Scaffolding Protein of the Corona of the Dictyostelium Centrosome". Cells 7 (4): 32. April 2018. doi:10.3390/cells7040032. PMID 29690637.
- ↑ "OMIM Entry - # 604804 - MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE; MCPH3". https://www.omim.org/entry/604804.
- ↑ "Identification of a common protein association region in the neuronal Cdk5 activator". The Journal of Biological Chemistry 275 (41): 31763–9. October 2000. doi:10.1074/jbc.M004358200. PMID 10915792.
- ↑ "Cloning of three novel neuronal Cdk5 activator binding proteins". Gene 242 (1–2): 285–94. January 2000. doi:10.1016/S0378-1119(99)00499-0. PMID 10721722.
Further reading
- "A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34". American Journal of Human Genetics 66 (2): 724–7. February 2000. doi:10.1086/302777. PMID 10677332.
- "Identification of a common protein association region in the neuronal Cdk5 activator". The Journal of Biological Chemistry 275 (41): 31763–9. October 2000. doi:10.1074/jbc.M004358200. PMID 10915792.
- "Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research 7 (4): 273–81. August 2000. doi:10.1093/dnares/7.4.271. PMID 10997877.
- "Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor". The Journal of Biological Chemistry 277 (18): 15237–40. May 2002. doi:10.1074/jbc.C200032200. PMID 11882646.
- "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Research 12 (11): 1773–84. November 2002. doi:10.1101/gr.406902. PMID 12421765.
- "Proteomic characterization of the human centrosome by protein correlation profiling". Nature 426 (6966): 570–4. December 2003. doi:10.1038/nature02166. PMID 14654843. Bibcode: 2003Natur.426..570A.
- "A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size". Nature Genetics 37 (4): 353–5. April 2005. doi:10.1038/ng1539. PMID 15793586.
- "Phosphoproteome analysis of the human mitotic spindle". Proceedings of the National Academy of Sciences of the United States of America 103 (14): 5391–6. April 2006. doi:10.1073/pnas.0507066103. PMID 16565220. Bibcode: 2006PNAS..103.5391N.
- "Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ". Gene 375: 75–9. June 2006. doi:10.1016/j.gene.2006.02.019. PMID 16631324.
- "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. November 2006. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
External links
- Human CDK5RAP2 genome location and CDK5RAP2 gene details page in the UCSC Genome Browser.
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