Structure of the Rb C-terminal domain bound to E2F1-DP1: A mechanism for phosphorylation-induced E2F release Journal Article

  

Authors:	Rubin, S. M.; Gall, A. L.; Zheng, N.; Pavletich, N. P.
Article Title:	Structure of the Rb C-terminal domain bound to E2F1-DP1: A mechanism for phosphorylation-induced E2F release
Abstract:	The retinoblastoma (Rb) protein negatively regulates the G1-S transition by binding to the E2F transcription factors, until cyclin-dependent kinases phosphorylate Rb, causing E2F release. The Rb pocket domain is necessary for E2F binding, but the Rb C-terminal domain (RbC) is also required for growth suppression. Here we demonstrate a high-affinity interaction between RbC and E2F-DP heterodimers shared by all Rb and E2F family members. The crystal structure of an RbC-E2F1-DP1 complex reveals an intertwined heterodimer in which the marked box domains of both E2F1 and DP1 contact RbC. We also demonstrate that phosphorylation of RbC at serines 788 and 795 destabilizes one set of RbC-E2F-DP interactions directly, while phosphorylation at threonines 821 and 826 induces an intramolecular interaction between RbC and the Rb pocket that destabilizes the remaining interactions indirectly. Our findings explain the requirement of RbC for high-affinity E2F binding and growth suppression and establish a mechanism for the regulation of Rb-E2F association by phosphorylation. ©2005 Elsevier Inc.
Keywords:	unclassified drug; dna-binding proteins; animals; models, biological; serine; carboxy terminal sequence; protein protein interaction; protein binding; transcription factor; phosphorylation; transcription factors; amino acid sequence; molecular sequence data; sequence homology, amino acid; peptide fragments; crystal structure; models, molecular; dimerization; crystallography, x-ray; protein structure, tertiary; threonine; multiprotein complexes; binding sites; protein structure; retinoblastoma protein; protein structure, quaternary; transcription factor e2f1; retinoblastoma-like protein p107; growth inhibition; transcription factor dp1; e2f1 transcription factor; e2f transcription factors
Journal Title:	Cell
Volume:	123
Issue:	6
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2005-12-16
Start Page:	1093
End Page:	1106
Language:	English
DOI:	10.1016/j.cell.2005.09.044
PUBMED:	16360038
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-28944437358&partnerID=40&md5=c82c6dff04ade913a984f4707a8af1ea
Notes:	--- - "Cited By (since 1996): 67" - "Export Date: 24 October 2012" - "CODEN: CELLB" - "Source: Scopus"

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