title: CDK5RAP2 is a pericentriolar protein that functions in centrosomal attachment of the gamma-tubulin ring complex.
abstract: Microtubule nucleation and organization by the centrosome require gamma-tubulin, a protein that exists in a macromolecular complex called the gamma-tubulin ring complex (gammaTuRC). 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 gamma-tubulin onto the centrosomes or under the microtubule-disrupting conditions into microtubule-nucleating clusters in the cytoplasm. CDK5RAP2 associates with the gammaTuRC 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 gammaTuRC attachment to the centrosome but not for gammaTuRC assembly. Perturbing CDK5RAP2 function delocalized gamma-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 gammaTuRC 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.
authors.affiliation: Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Fong
authors.forename: Yuk-Kwan
authors.initials: YK
authors.lastname: Choi
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Rattner
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Qi
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism* / Q000648:ultrastructure; D017124:Conserved Sequence; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D008941:Spindle Apparatus / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*
chemical_list: C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014404:Tubulin