CDK5RAP2
Identifiers
AliasesCDK5RAP2, C48, Cep215, MCPH3, CDK5 regulatory subunit associated protein 2
External IDsOMIM: 608201 MGI: 2384875 HomoloGene: 49533 GeneCards: CDK5RAP2
Orthologs
SpeciesHumanMouse
Entrez

55755

214444

Ensembl

ENSG00000136861

ENSMUSG00000039298

UniProt

Q96SN8

P68254
Q8K389

RefSeq (mRNA)

NM_001011649
NM_001272039
NM_018249

NM_145990
NM_001313762

RefSeq (protein)

NP_001011649
NP_001258968
NP_060719

NP_035869
NP_001300691
NP_666102

Location (UCSC)Chr 9: 120.39 – 120.58 MbChr 4: 70.14 – 70.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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[5] and has been found to be linked to human brain size variation in males.[6] Multiple transcript variants exist for this gene, but the full-length nature of only two has been determined.[7][8]

CDK5RAP2 is homologous to the Drosophila protein centrosomin (cnn)[9] and paralogous to myomegalin, which in mammals contains an Olduvai domain, a domain implicated in human brain size evolution.[10][11]

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.[5] 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.[8] CDK5RAP2 is also necessary as a scaffolding protein in the centrosomal corona of Dictyostelium.[12]

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.[6] 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.[10][11]

Autosomal recessive primary microcephaly

Mutations in CDK5RAP2 cause autosomal recessive primary microcephaly type 3.[13][5]

Interactions

CDK5RAP2 has been shown to interact with CDK5R1[14] and pericentrin (PCTN).[8]

History

The gene was discovered in 2000[15] and was first characterised in 2007.[5]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000136861 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039298 - 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. 1 2 3 4 Fong KW, Choi YK, Rattner JB, Qi RZ (January 2008). "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. doi:10.1091/mbc.E07-04-0371. PMC 2174194. PMID 17959831.
  6. 1 2 Rimol LM, Agartz I, Djurovic S, Brown AA, Roddey JC, Kähler AK, et al. (January 2010). "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. Bibcode:2010PNAS..107..384R. doi:10.1073/pnas.0908454107. PMC 2806758. PMID 20080800.
  7. ↑ Ching YP, Qi Z, Wang JH (January 2000). "Cloning of three novel neuronal Cdk5 activator binding proteins". Gene. 242 (1–2): 285–94. doi:10.1016/S0378-1119(99)00499-0. PMID 10721722.
  8. 1 2 3 "Entrez Gene: CDK5RAP2 CDK5 regulatory subunit associated protein 2".
  9. ↑ Barr AR, Kilmartin JV, Gergely F (April 2010). "CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response". The Journal of Cell Biology. 189 (1): 23–39. doi:10.1083/jcb.200912163. PMC 2854379. PMID 20368616.
  10. 1 2 Dumas L, Kim YH, Karimpour-Fard A, Cox M, Hopkins J, Pollack JR, Sikela JM (September 2007). "Gene copy number variation spanning 60 million years of human and primate evolution". Genome Research. 17 (9): 1266–77. doi:10.1101/gr.6557307. PMC 1950895. PMID 17666543.
  11. 1 2 O'Bleness MS, Dickens CM, Dumas LJ, Kehrer-Sawatzki H, Wyckoff GJ, Sikela JM (September 2012). "Evolutionary history and genome organization of DUF1220 protein domains". G3. 2 (9): 977–86. doi:10.1534/g3.112.003061. PMC 3429928. PMID 22973535.
  12. ↑ Pitzen V, Askarzada S, Gräf R, Meyer I (April 2018). "CDK5RAP2 Is an Essential Scaffolding Protein of the Corona of the Dictyostelium Centrosome". Cells. 7 (4): 32. doi:10.3390/cells7040032. PMC 5946109. PMID 29690637.
  13. ↑ "OMIM Entry - # 604804 - MICROCEPHALY 3, PRIMARY, AUTOSOMAL RECESSIVE; MCPH3". www.omim.org. Retrieved 2020-01-06.
  14. ↑ Wang X, Ching YP, Lam WH, Qi Z, Zhang M, Wang JH (October 2000). "Identification of a common protein association region in the neuronal Cdk5 activator". The Journal of Biological Chemistry. 275 (41): 31763–9. doi:10.1074/jbc.M004358200. PMID 10915792.
  15. ↑ Ching YP, Qi Z, Wang JH (January 2000). "Cloning of three novel neuronal Cdk5 activator binding proteins". Gene. 242 (1–2): 285–94. doi:10.1016/S0378-1119(99)00499-0. PMID 10721722.

Further reading

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