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Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control.

Authors
  • Burke, Jason R1
  • Hura, Greg L
  • Rubin, Seth M
  • 1 Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, California 95064, USA.
Type
Published Article
Journal
Genes & development
Publication Date
Jun 01, 2012
Volume
26
Issue
11
Pages
1156–1166
Identifiers
DOI: 10.1101/gad.189837.112
PMID: 22569856
Source
Medline
Language
English
License
Unknown

Abstract

Cyclin-dependent kinase (Cdk) phosphorylation of the Retinoblastoma protein (Rb) drives cell proliferation through inhibition of Rb complexes with E2F transcription factors and other regulatory proteins. We present the first structures of phosphorylated Rb that reveal the mechanism of its inactivation. S608 phosphorylation orders a flexible "pocket" domain loop such that it mimics and directly blocks E2F transactivation domain (E2F(TD)) binding. T373 phosphorylation induces a global conformational change that associates the pocket and N-terminal domains (RbN). This first multidomain Rb structure demonstrates a novel role for RbN in allosterically inhibiting the E2F(TD)-pocket association and protein binding to the pocket "LxCxE" site. Together, these structures detail the regulatory mechanism for a canonical growth-repressive complex and provide a novel example of how multisite Cdk phosphorylation induces diverse structural changes to influence cell cycle signaling.

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