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Vol. 19, Issue 1, 115-125, January 2008

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CDK5RAP2 Is a Pericentriolar Protein That Functions in Centrosomal Attachment of the -Tubulin Ring Complex

Ka-Wing Fong^*, Yuk-Kwan Choi^*, Jerome B. Rattner, and Robert Z. Qi^*

*Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; and Department of Cell Biology and Anatomy, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Submitted April 24, 2007; Revised September 6, 2007; Accepted October 16, 2007
Monitoring Editor: Stephen Doxsey

Microtubule nucleation and organization by the centrosome require -tubulin, a protein that exists in a macromolecular complex called the -tubulin ring complex (TuRC). We report characterization of CDK5RAP2, a novel centrosomal protein whose mutations have been linked to autosomal recessive primary microcephaly. In somatic cells, CDK5RAP2 localizes throughout the pericentriolar material in all stages of the cell cycle. When overexpressed, CDK5RAP2 assembled a subset of centrosomal proteins including -tubulin onto the centrosomes or under the microtubule-disrupting conditions into microtubule-nucleating clusters in the cytoplasm. CDK5RAP2 associates with the TuRC via a short conserved sequence present in several related proteins found in a range of organisms from fungi to mammals. The binding of CDK5RAP2 is required for TuRC attachment to the centrosome but not for TuRC assembly. Perturbing CDK5RAP2 function delocalized -tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in TuRC attachment and therefore in the microtubule organizing function of the centrosome. Our findings suggest that centrosome malfunction due to the CDK5RAP2 mutations may underlie autosomal recessive primary microcephaly.

Address correspondence to: Robert Z. Qi (qirz{at}ust.hk)

Abbreviations used: MT, microtubule; MTOC, microtubule-organizing center; PCM, pericentriolar material; TuRC, -tubulin ring complex; TuC, -tubulin complex; GCP, -tubulin complex protein; MCPH, autosomal recessive primary microcephaly; Cnn, centrosomin; PDE4DIP, phosphodiesterase 4D-interacting protein.