| Structural highlights
Disease
[CEP63_HUMAN] Autosomal recessive primary microcephaly. The disease is caused by mutations affecting the gene represented in this entry.
Function
[CEP63_HUMAN] Required for normal spindle assembly. Plays a key role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication. Reported to be required for centrosomal recruitment of CEP152; however, this function has been questioned (PubMed:21983783, PubMed:26297806). Also recruits CDK1 to centrosomes (PubMed:21406398). Plays a role in DNA damage response. Following DNA damage, such as double-strand breaks (DSBs), is removed from centrosomes; this leads to the inactivation of spindle assembly and delay in mitotic progression (PubMed:21406398).[1] [2] [3]
Publication Abstract from PubMed
The cell is constructed by higher-order structures and organelles through complex interactions among distinct structural constituents. The centrosome is a membraneless organelle composed of two microtubule-derived structures called centrioles and an amorphous mass of pericentriolar material. Super-resolution microscopic analyses in various organisms revealed that diverse pericentriolar material proteins are concentrically localized around a centriole in a highly organized manner. However, the molecular nature underlying these organizations remains unknown. Here we show that two human pericentriolar material scaffolds, Cep63 and Cep152, cooperatively generate a heterotetrameric alpha-helical bundle that functions in conjunction with its neighboring hydrophobic motifs to self-assemble into a higher-order cylindrical architecture capable of recruiting downstream components, including Plk4, a key regulator for centriole duplication. Mutations disrupting the self-assembly abrogate Plk4-mediated centriole duplication. Because pericentriolar material organization is evolutionarily conserved, this work may offer a paradigm for investigating the assembly and function of centrosomal scaffolds in various organisms.
Molecular architecture of a cylindrical self-assembly at human centrosomes.,Kim TS, Zhang L, Il Ahn J, Meng L, Chen Y, Lee E, Bang JK, Lim JM, Ghirlando R, Fan L, Wang YX, Kim BY, Park JE, Lee KS Nat Commun. 2019 Mar 11;10(1):1151. doi: 10.1038/s41467-019-08838-2. PMID:30858376[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Loffler H, Fechter A, Matuszewska M, Saffrich R, Mistrik M, Marhold J, Hornung C, Westermann F, Bartek J, Kramer A. Cep63 recruits Cdk1 to the centrosome: implications for regulation of mitotic entry, centrosome amplification, and genome maintenance. Cancer Res. 2011 Mar 15;71(6):2129-39. doi: 10.1158/0008-5472.CAN-10-2684. PMID:21406398 doi:http://dx.doi.org/10.1158/0008-5472.CAN-10-2684
- ↑ Sir JH, Barr AR, Nicholas AK, Carvalho OP, Khurshid M, Sossick A, Reichelt S, D'Santos C, Woods CG, Gergely F. A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet. 2011 Oct 9;43(11):1147-53. doi: 10.1038/ng.971. PMID:21983783 doi:http://dx.doi.org/10.1038/ng.971
- ↑ Kodani A, Yu TW, Johnson JR, Jayaraman D, Johnson TL, Al-Gazali L, Sztriha L, Partlow JN, Kim H, Krup AL, Dammermann A, Krogan NJ, Walsh CA, Reiter JF. Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication. Elife. 2015 Aug 22;4. doi: 10.7554/eLife.07519. PMID:26297806 doi:http://dx.doi.org/10.7554/eLife.07519
- ↑ Kim TS, Zhang L, Il Ahn J, Meng L, Chen Y, Lee E, Bang JK, Lim JM, Ghirlando R, Fan L, Wang YX, Kim BY, Park JE, Lee KS. Molecular architecture of a cylindrical self-assembly at human centrosomes. Nat Commun. 2019 Mar 11;10(1):1151. doi: 10.1038/s41467-019-08838-2. PMID:30858376 doi:http://dx.doi.org/10.1038/s41467-019-08838-2
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