2r7g
From Proteopedia
Structure of the retinoblastoma protein pocket domain in complex with adenovirus E1A CR1 domain
Structural highlights
Disease[RB_HUMAN] Defects in RB1 are the cause of childhood cancer retinoblastoma (RB) [MIM:180200]. RB is a congenital malignant tumor that arises from the nuclear layers of the retina. It occurs in about 1:20'000 live births and represents about 2% of childhood malignancies. It is bilateral in about 30% of cases. Although most RB appear sporadically, about 20% are transmitted as an autosomal dominant trait with incomplete penetrance. The diagnosis is usually made before the age of 2 years when strabismus or a gray to yellow reflex from pupil ('cat eye') is investigated.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Defects in RB1 are a cause of susceptibility to bladder cancer (BLC) [MIM:109800]. A malignancy originating in tissues of the urinary bladder. It often presents with multiple tumors appearing at different times and at different sites in the bladder. Most bladder cancers are transitional cell carcinomas. They begin in cells that normally make up the inner lining of the bladder. Other types of bladder cancer include squamous cell carcinoma (cancer that begins in thin, flat cells) and adenocarcinoma (cancer that begins in cells that make and release mucus and other fluids). Bladder cancer is a complex disorder with both genetic and environmental influences. Defects in RB1 are a cause of osteogenic sarcoma (OSRC) [MIM:259500]. Function[RB_HUMAN] Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, SUV420H1 and SUV420H2, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity). In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.[14] [E1A_ADE05] E1A protein has both transforming and trans-activating activities. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle. Disrupts the function of host retinoblastoma protein RB1/pRb and isoform early E1A 26 kDa protein stabilizes TP53, which are key regulators of the cell cycle. Induces the disassembly of the E2F1 transcription factors from RB1 by direct competition for the same binding site on RB1, with subsequent transcriptional activation of E2F1-regulated S-phase genes. Inactivation of the ability of RB1 to arrest the cell cycle is critical for cellular transformation, uncontrolled cellular growth and proliferation induced by viral infection. Stimulation of progression from G1 to S phase allows the virus to efficiently use the cellular DNA replicating machinery to achieve viral genome replication. Interaction with RBX1 and CUL1 inhibits ubiquitination of the proteins targeted by SCF(FBW7) ubiquitin ligase complex, and may be linked to unregulated host cell proliferation. The tumorigenesis-restraining activity of E1A may be related to the disruption of the host CtBP-CtIP complex through the CtBP binding motif.[15] [16] [17] [18] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe adenovirus (Ad) E1A (Ad-E1A) oncoprotein mediates cell transformation, in part, by displacing E2F transcription factors from the retinoblastoma protein (pRb) tumor suppressor. In this study we determined the crystal structure of the pRb pocket domain in complex with conserved region 1 (CR1) of Ad5-E1A. The structure and accompanying biochemical studies reveal that E1A-CR1 binds at the interface of the A and B cyclin folds of the pRb pocket domain, and that both E1A-CR1 and the E2F transactivation domain use similar conserved nonpolar residues to engage overlapping sites on pRb, implicating a novel molecular mechanism for pRb inactivation by a viral oncoprotein. Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor.,Liu X, Marmorstein R Genes Dev. 2007 Nov 1;21(21):2711-6. PMID:17974914[19] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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