2MKF
Solution structure of the E81 deletion mutant of the tandem UIMs of RAP80
Summary for 2MKF
| Entry DOI | 10.2210/pdb2mkf/pdb |
| Related | 2MKG 3A1Q |
| NMR Information | BMRB: 19773 |
| Descriptor | BRCA1-A complex subunit RAP80 (1 entity in total) |
| Functional Keywords | uim, ubiquitin-interacting motif, dna damage response, signaling protein |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus: Q96RL1 |
| Total number of polymer chains | 1 |
| Total formula weight | 6889.58 |
| Authors | Anamika,Markin, C.J.,Rout, M.K.,Spyracopoulos, L. (deposition date: 2014-02-06, release date: 2014-03-19, Last modification date: 2024-05-15) |
| Primary citation | Anamika,Markin, C.J.,Rout, M.K.,Spyracopoulos, L. Molecular Basis for Impaired DNA Damage Response Function Associated with the RAP80 Delta E81 Defect. J.Biol.Chem., 289:12852-12862, 2014 Cited by PubMed Abstract: Signal 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 Lys-63-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 concomitant role in the pathogenesis of cancer. Recently, an in-frame deletion mutation (ΔE81) in a conserved region from the first ubiquitin interaction motif of RAP80 has been linked to an increase in chromosomal abnormalities. Using NMR spectroscopy, we demonstrate that the N-cap motif within the α-helix of the first ubiquitin interaction motif from ΔE81 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. PubMed: 24627472DOI: 10.1074/jbc.M113.538280 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
Download full validation report
