2mkf | pdb_00002mkf
Solution structure of the E81 deletion mutant of the tandem UIMs of RAP80
Structural highlights
FunctionUIMC1_HUMAN Ubiquitin-binding protein that specifically recognizes and binds 'Lys-63'-linked ubiquitin. Plays a central role in the BRCA1-A complex by specifically binding 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. Also weakly binds monoubiquitin but with much less affinity than 'Lys-63'-linked ubiquitin. May interact with monoubiquitinated histones H2A and H2B; the relevance of such results is however unclear in vivo. Does not bind Lys-48'-linked ubiquitin. May indirectly act as a transcriptional repressor by inhibiting the interaction of NR6A1 with the corepressor NCOR1.[1] [2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedSignal transduction within the DNA damage response is driven by the flux of protein-protein interaction cascades that ultimately recruit repair complexes to sites of damage. The protein RAP80 plays a central role in the damage response by targeting BRCA1/BRCA2 tumor suppressors to DNA damage foci through multivalent binding of K63-linked polyubiquitin chains. Mutations within the high penetrance BRCA1/BRCA2 genes account for ~20% of familial breast cancers. The genetic basis for the remaining cancers remains unknown, but may involve defects in binding partners for BRCA1 and BRCA2 that lead to impaired targeting to foci and a concomittant role in the pathogenesis of cancer. Recently, an in-frame deletion mutation (DeltaE81) in a conserved region from the first ubiquitin interaction motif (UIM) of RAP80 has been linked to an increase in chromosomal abnormalities. Using NMR spectroscopy, we demonstrate that the N-cap motif within the Delta-helix of the first UIM from DeltaE81 undergoes a structural frameshift that leads to abolishment of multivalent binding of polyubiquitin chains. Loss of this single glutamate residue disrupts favorable electrostatic interactions between RAP80 and ubiquitin, establishing a plausible molecular basis for a potential predisposition to cancer unrelated to mutations within BRCA1/BRCA2 genes. Molecular Basis for Impaired DNA Damage Response Function Associated with the RAP80 DeltaE81 Defect.,Anamika A, Markin CJ, Rout MK, Spyracopoulos L J Biol Chem. 2014 Mar 13. PMID:24627472[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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