5u6k
From Proteopedia
Crystal structure of TopBP1 BRCT4/5 in complex with a BLM phosphopeptide
Structural highlights
FunctionTOPB1_MOUSE Required for DNA replication (By similarity). Plays a role in the rescue of stalled replication forks and checkpoint control (PubMed:14718568). Binds double-stranded DNA breaks and nicks as well as single-stranded DNA (By similarity). Recruits the SWI/SNF chromatin remodeling complex to E2F1-responsive promoters. Down-regulates E2F1 activity and inhibits E2F1-dependent apoptosis during G1/S transition and after DNA damage (By similarity). Induces a large increase in the kinase activity of ATR (By similarity).[UniProtKB:Q92547][1] Publication Abstract from PubMedTopoisomerase IIbeta binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1. Structural Insight into BLM Recognition by TopBP1.,Sun L, Huang Y, Edwards RA, Yang S, Blackford AN, Niedzwiedz W, Glover JNM Structure. 2017 Sep 1. pii: S0969-2126(17)30258-7. doi:, 10.1016/j.str.2017.08.005. PMID:28919440[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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