Insights from the crystal structure of the sixth BRCT domain of topoisomerase II[beta] binding protein 1

• Published in: Protein science Vol. 19; no. 1; p. 162
• Main Authors: Leung, Charles Chung Yun, Kellogg, Elizabeth, Kuhnert, Anja, Hanel, Frank, Baker, David, Glover, J N Mark
• Format: Journal Article
• Language: English
• Published: Bethesda Wiley Subscription Services, Inc 01.01.2010
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.290

Topoisomerase II[beta] binding protein 1 (TopBP1) is a major player in the DNA damage response and interacts with a number of protein partners via its eight BRCA1 carboxy-terminal (BRCT) domains. In particular, the sixth BRCT domain of TopBP1 has been implicated in binding to the phosphorylated transcription factor, E2F1, and poly(ADP-ribose) polymerase 1 (PARP-1), where the latter interaction is responsible for the poly(ADP-ribosyl)ation of TopBP1. To gain a better understanding of the nature of TopBP1 BRCT6 interactions, we solved the crystal structure of BRCT6 to 1.34 Å. The crystal structure reveals a degenerate phospho-peptide binding pocket and lacks conserved hydrophobic residues involved in packing of tandem BRCT repeats, which, together with results from phospho-peptide binding studies, strongly suggest that TopBP1 BRCT6 independently does not function as a phospho-peptide binding domain. We further provide insight into poly(ADP-ribose) binding and sites of potential modification by PARP-1.