NDLI: Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation

Content Provider	PubMed Central
Author	Xiao, Bing Spencer, James Clements, Adrienne Ali Khan, Nadeem Mittnacht, Sibylle Broceño, Cristina Manfred, Burghammer Perrakis, Anastassis Marmorstein, Ronen Gamblin, Steven J.
Copyright Year	2003
Abstract	The retinoblastoma tumor suppressor protein (pRb) regulates the cell cycle, facilitates differentiation, and restrains apoptosis. Furthermore, dysfunctional pRb is thought to be involved in the development of most human malignancies. Many of the functions of pRb are mediated by its regulation of the E2F transcription factors. To understand the structural basis for this regulation, we have determined the crystal structure of a fragment of E2F in complex with the pocket domain of the tumor suppressor protein. The pRb pocket, comprising the A and B cyclin-like domains, is the major focus of tumourigenic mutations in the protein. The fragment of E2F used in our structural studies, residues 409–426 of E2F-1, represents the core of the pRb-binding region of the transcription factor. The structure shows that E2F binds at the interface of the A and B domains of the pocket making extensive interactions with conserved residues from both. We show by solution studies that a second site, probably contained within the “marked box” region of E2F, is responsible for additional interactions with the pRb pocket but is insufficient for complex formation on its own. In addition, we show that the interaction of the core binding fragment of E2F with pRb is inhibited by phosphorylation of the tumor suppressor protein by CDK2/cyclin D/E. Finally, our data reveal that the tight binding of the human papillomavirus E7 oncoprotein to pRb prevents subsequent interactions with the marked box region of E2F but not with its core binding region.
Related Links	http://dx.doi.org/10.1073/pnas.0436813100
Ending Page	2368
Page Count	6
Starting Page	2363
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	5
Volume Number	100
Language	English
Publisher	The National Academy of Sciences
Publisher Date	2003-03-04
Access Restriction	Open
Rights Holder	The National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.

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