CDK5RAP2

Last updated

CDK5RAP2
Identifiers
Aliases CDK5RAP2 , C48, Cep215, MCPH3, CDK5 regulatory subunit associated protein 2
External IDs OMIM: 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 Mb Chr 4: 70.22 – 70.41 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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]

Contents

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]

Related Research Articles

CDK5R1

Cyclin-dependent kinase 5 activator 1 is an enzyme that in humans is encoded by the CDK5R1 gene.

NEK2

Serine/threonine-protein kinase Nek2 is an enzyme that in humans is encoded by the NEK2 gene.

Ninein

Ninein is a protein that in humans is encoded by the NIN gene. Ninein, together with its paralog Ninein-like protein is one of the proteins important for centrosomal function. This protein is important for positioning and anchoring the microtubules minus-ends in epithelial cells. Localization of this protein to the centrosome requires three leucine zippers in the central coiled-coil domain. Multiple alternatively spliced transcript variants that encode different isoforms have been reported.

CENPJ Centromere- and microtubule-associated protein

Centromere protein J is a protein that in humans is encoded by the CENPJ gene. It is also known as centrosomal P4.1-associated protein (CPAP). During cell division, this protein plays a structural role in the maintenance of centrosome integrity and normal spindle morphology, and it is involved in microtubule disassembly at the centrosome. This protein can function as a transcriptional coactivator in the Stat5 signaling pathway and also as a coactivator of NF-kappaB-mediated transcription, likely via its interaction with the coactivator p300/CREB-binding protein.

CDK5RAP3

CDK5 regulatory subunit-associated protein 3 is a protein that in humans is encoded by the CDK5RAP3 gene.

CEP350

Centrosome-associated protein 350 is a protein that in humans is encoded by the CEP350 gene.

CDK5RAP1

CDK5 regulatory subunit-associated protein 1 is a protein that in humans is encoded by the CDK5RAP1 gene.

CDK5R2

Cyclin-dependent kinase 5 activator 2 is an enzyme that in humans is encoded by the CDK5R2 gene.

CEP68

Centrosomal protein of 68 kDa is a protein that in humans is encoded by the CEP68 gene. CEP68 is required for centrosome cohesion. It decorates fibres emanating from the proximal ends of centrioles. During mitosis, CEP68 dissociates from centrosomes. CEP68 and rootletin depend both on each other for centriole association, and both also require CEP250 for their function.

Myomegalin Vertebrate protein involved in the formation of microtubules

Myomegalin, also known as phosphodiesterase 4D-interacting protein or cardiomyopathy-associated protein 2, is a protein that in humans is encoded by the PDE4DIP gene. It has roles in the formation of microtubules from the centrosome. Its name derives from the fact that it is highly expressed in units of tubular myofibrils known as sarcomeres and is a large protein, at 2,324 amino acids. It was first characterised in 2000.

CCP110

Centriolar coiled-coil protein of 110 kDa also known as centrosomal protein of 110 kDa or CP110 is a protein that in humans is encoded by the CCP110 gene. It is a cell cycle-dependent CDK substrate and regulates centrosome duplication. CP110 suppresses a cilia assembly program.

Cyclin-dependent kinase 5

Cyclin dependent kinase 5 is a protein, and more specifically an enzyme, that is encoded by the Cdk5 gene. It was discovered 15 years ago and it is saliently expressed in post-mitotic central nervous system neurons (CNS).

CEP135

Centrosomal protein of 135 kDa is a protein that in humans is encoded by the CEP135 gene. It is part of the centrosome throughout the cell cycle, being distributed in the pericentriolar material. CEP135 is required for the centriolar localization of CEP250.

Rootletin

Rootletin also known as ciliary rootlet coiled-coil protein (CROCC) is a protein that in humans is encoded by the CROCC gene. Rootletin is a component of the ciliary rootlet, and, together with CEP68 and CEP250, is required for centrosome cohesion.

CEP192

Centrosomal protein of 192 kDa, also known as Cep192, is a protein that in humans is encoded by the CEP192 gene. It is the homolog of the C. elegans and D. melanogaster gene SPD-2.

CEP164

Centrosomal protein of 164 kDa, also known as CEP164, is a protein that in humans is encoded by the CEP164 gene. Its function appears two be twofold: CEP164 is required for primary cilium formation. Furthermore, it is an important component in the response to DNA damage by UV light.

CEP76

Centrosomal protein of 76 kDa, also known as CEP76, is a protein that in humans is encoded by the CEP76 gene.

CEP78

Centrosomal protein of 78 kDa, also known as Cep78, is a protein that in humans is encoded by the CEP78 gene.

CEP152

Centrosomal protein of 152 kDa, also known as Cep152, is a protein that in humans is encoded by the CEP152 gene. It is the ortholog of the Drosophila melanogaster gene asterless (asl) and both are required for centriole duplication.

CDKAL1

CDKAL1 is a gene in the methylthiotransferase family. The complete physiological function and implications of this have not been fully determined. CDKAL1 is known to code for CDK5, a regulatory subunit-associated protein 1. This protein CDK5 regulatory subunit-associated protein 1 is found broadly across tissue types including neuronal tissues and pancreatic beta cells. CDKAL1 is suspected to be involved in the CDK5/p35 pathway, in which p35 is the activator for CDK5 which regulates several neuronal functions.

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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