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The structure of CDK4/cyclin D3 has implications for models of CDK activation

Lookup NU author(s): Professor Jane Endicott, Professor Martin Noble

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Abstract

Cyclin-dependent kinase 4 (CDK4)/cyclin D complexes are expressed early in the G1 phase of the cell cycle and stimulate the expression of genes required for G1 progression by phosphorylation of the product of the retinoblastoma gene, pRb. To elaborate the molecular pathway of CDK4 activation and substrate selection we have determined the structure of nonphosphorylated CDK4/cyclin D3. This structure of an authentic CDK/cyclin complex shows that cyclin binding may not be sufficient to drive the CDK active site toward an active conformation. Phosphorylated CDK4/cyclin D3 is active as a pRb kinase and is susceptible to inhibition by p27Kip1. Unlike CDK2/cyclin A, CDK4/cyclin D3 can be inactivated by treatment with lambda-phosphatase, implying that phosphorylated T172 is accessible to a generic phosphatase while bound to a cyclin. Taken together, these results suggest that the structural mechanism of CDK4/cyclin D3 activation differs markedly from that of previously studied CDK/cyclin complexes.


Publication metadata

Author(s): Takaki T, Echalier A, Brown NR, Hunt T, Endicott JA, Noble MEM

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences

Year: 2009

Volume: 106

Issue: 11

Pages: 4171-4176

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: http://dx.doi.org/10.1073/pnas.0809674106

DOI: 10.1073/pnas.0809674106


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