Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation
AUTOR(ES)
Xiao, Bing
FONTE
The National Academy of Sciences
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=151346Documentos Relacionados
- Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor
- Clefts, grooves, and (small) pockets: The structure of the retinoblastoma tumor suppressor in complex with its cellular target E2F unveiled
- The human papillomavirus E7 oncoprotein and the cellular transcription factor E2F bind to separate sites on the retinoblastoma tumor suppressor protein.
- Regulation of E2F through ubiquitin–proteasome-dependent degradation: Stabilization by the pRB tumor suppressor protein
- The retinoblastoma protein binds to a family of E2F transcription factors.