CDK5RAP2 explained

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. Multiple transcript variants exist for this gene, but the full-length nature of only two has been determined.^{[2] [3]}

CDK5RAP2 is homologous to the Drosophila protein centrosomin (cnn)^[4] and paralogous to myomegalin, which in mammals contains an Olduvai domain, a domain implicated in human brain size evolution.^{[5] [6]}

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. 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. CDK5RAP2 is also necessary as a scaffolding protein in the centrosomal corona of Dictyostelium.^[7]

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.^[8] 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.

Autosomal recessive primary microcephaly

Mutations in CDK5RAP2 cause autosomal recessive primary microcephaly type 3.^[9]

Interactions

CDK5RAP2 has been shown to interact with CDK5R1^[10] and pericentrin (PCTN).

History

The gene was discovered in 2000^[11] and was first characterised in 2007.

Further reading

• Moynihan L, Jackson AP, Roberts E, Karbani G, Lewis I, Corry P, Turner G, Mueller RF, Lench NJ, Woods CG . 6 . A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34 . American Journal of Human Genetics . 66 . 2 . 724–7 . February 2000 . 10677332 . 1288125 . 10.1086/302777 .
• Wang X, Ching YP, Lam WH, Qi Z, Zhang M, Wang JH . Identification of a common protein association region in the neuronal Cdk5 activator . The Journal of Biological Chemistry . 275 . 41 . 31763–9 . October 2000 . 10915792 . 10.1074/jbc.M004358200 . free .
• Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O . 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 . 10997877 . 10.1093/dnares/7.4.271 . free .
• Ching YP, Pang AS, Lam WH, Qi RZ, Wang JH . Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor . The Journal of Biological Chemistry . 277 . 18 . 15237–40 . May 2002 . 11882646 . 10.1074/jbc.C200032200 . free .
• Nakayama M, Kikuno R, Ohara O . 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 . 12421765 . 187542 . 10.1101/gr.406902 .
• Andersen JS, Wilkinson CJ, Mayor T, Mortensen P, Nigg EA, Mann M . Proteomic characterization of the human centrosome by protein correlation profiling . Nature . 426 . 6966 . 570–4 . December 2003 . 14654843 . 10.1038/nature02166 . 2003Natur.426..570A . 4427303 .
• Bond J, Roberts E, Springell K, Lizarraga SB, Lizarraga S, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG . 6 . A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size . Nature Genetics . 37 . 4 . 353–5 . April 2005 . 15793586 . 10.1038/ng1539 . 1763877 .
• Nousiainen M, Silljé HH, Sauer G, Nigg EA, Körner R . 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 . 16565220 . 1459365 . 10.1073/pnas.0507066103 . 2006PNAS..103.5391N . free .
• Evans PD, Vallender EJ, Lahn BT . Molecular evolution of the brain size regulator genes CDK5RAP2 and CENPJ . Gene . 375 . 75–9 . June 2006 . 16631324 . 10.1016/j.gene.2006.02.019 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Fong KW, Choi YK, Rattner JB, Qi RZ . 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 . 17959831 . 2174194 . 10.1091/mbc.E07-04-0371 .
2. Ching YP, Qi Z, Wang JH . Cloning of three novel neuronal Cdk5 activator binding proteins . Gene . 242 . 1–2 . 285–94 . January 2000 . 10721722 . 10.1016/S0378-1119(99)00499-0 .
3. Web site: Entrez Gene: CDK5RAP2 CDK5 regulatory subunit associated protein 2.
4. Barr AR, Kilmartin JV, Gergely F . CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response . The Journal of Cell Biology . 189 . 1 . 23–39 . April 2010 . 20368616 . 2854379 . 10.1083/jcb.200912163 .
5. Dumas L, Kim YH, Karimpour-Fard A, Cox M, Hopkins J, Pollack JR, Sikela JM . Gene copy number variation spanning 60 million years of human and primate evolution . Genome Research . 17 . 9 . 1266–77 . September 2007 . 17666543 . 1950895 . 10.1101/gr.6557307 .
6. O'Bleness MS, Dickens CM, Dumas LJ, Kehrer-Sawatzki H, Wyckoff GJ, Sikela JM . Evolutionary history and genome organization of DUF1220 protein domains . G3 . 2 . 9 . 977–86 . September 2012 . 22973535 . 3429928 . 10.1534/g3.112.003061 .
7. Pitzen V, Askarzada S, Gräf R, Meyer I . CDK5RAP2 Is an Essential Scaffolding Protein of the Corona of the Dictyostelium Centrosome . Cells . 7 . 4 . April 2018 . 32 . 29690637 . 5946109 . 10.3390/cells7040032 . free .
8. Rimol LM, Agartz I, Djurovic S, Brown AA, Roddey JC, Kähler AK, Mattingsdal M, Athanasiu L, Joyner AH, Schork NJ, Halgren E, Sundet K, Melle I, Dale AM, Andreassen OA . 6 . 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 . 20080800 . 2806758 . 10.1073/pnas.0908454107 . 2010PNAS..107..384R . free .
9. Web site: OMIM Entry - # 604804 - MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE; MCPH3. www.omim.org. 2020-01-06.
10. Wang X, Ching YP, Lam WH, Qi Z, Zhang M, Wang JH . Identification of a common protein association region in the neuronal Cdk5 activator . The Journal of Biological Chemistry . 275 . 41 . 31763–9 . October 2000 . 10915792 . 10.1074/jbc.M004358200 . free .
11. Ching YP, Qi Z, Wang JH . Cloning of three novel neuronal Cdk5 activator binding proteins . Gene . 242 . 1–2 . 285–94 . January 2000 . 10721722 . 10.1016/S0378-1119(99)00499-0 .