Pitchai Ganesha P, Kaulich Manuel, Bizard Anna H, Mesa Pablo, Yao Qi, Sarlos Kata, Streicher Werner W, Nigg Erich A, Montoya Guillermo, Hickson Ian D
Novo Nordisk Foundation Center for Protein Research, Protein Structure & Function Programme, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Nucleic Acids Res. 2017 Nov 2;45(19):11413-11424. doi: 10.1093/nar/gkx792.
PICH is a DNA translocase required for the maintenance of chromosome stability in human cells. Recent data indicate that PICH co-operates with topoisomerase IIα to suppress pathological chromosome missegregation through promoting the resolution of ultra-fine anaphase bridges (UFBs). Here, we identify the BEN domain-containing protein 3 (BEND3) as an interaction partner of PICH in human cells in mitosis. We have purified full length PICH and BEND3 and shown that they exhibit a functional biochemical interaction in vitro. We demonstrate that the PICH-BEND3 interaction occurs via a novel interface between a TPR domain in PICH and a BEN domain in BEND3, and have determined the crystal structure of this TPR-BEN complex at 2.2 Å resolution. Based on the structure, we identified amino acids important for the TPR-BEN domain interaction, and for the functional interaction of the full-length proteins. Our data reveal a proposed new function for BEND3 in association with PICH, and the first example of a specific protein-protein interaction mediated by a BEN domain.
PICH是人类细胞维持染色体稳定性所需的一种DNA转位酶。最近的数据表明，PICH与拓扑异构酶IIα协同作用，通过促进超微后期桥（UFBs）的解离来抑制病理性染色体错分离。在此，我们鉴定出含BEN结构域蛋白3（BEND3）是有丝分裂期人类细胞中PICH的相互作用伴侣。我们纯化了全长PICH和BEND3，并表明它们在体外表现出功能性生化相互作用。我们证明PICH-BEND3相互作用通过PICH中一个TPR结构域与BEND3中一个BEN结构域之间的新界面发生，并以2.2 Å分辨率确定了该TPR-BEN复合物的晶体结构。基于该结构，我们鉴定出了对TPR-BEN结构域相互作用以及全长蛋白功能相互作用重要的氨基酸。我们的数据揭示了BEND3与PICH相关的一种新功能，以及由BEN结构域介导的特异性蛋白质-蛋白质相互作用的首个实例。
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