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Structural and functional insights into the role of the N-terminal Mps1 TPR domain in the SAC (spindle assembly checkpoint)

DOI: 10.1042/BJ20121448 DOI Help
PMID: 23067341 PMID Help

Authors: Philippe Thebault (Centre de Recherche du CHUQ) , Dimitri Y. Chirgadze (University of Cambridge) , Zhen Dou (University of Science and Technology of China) , Tom Blundell (University of Cambridge) , Sabine Elowe (Université Laval) , Victor Bolanos-garcia (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal , VOL 448 , PAGES 321 - 328

State: Published (Approved)
Published: December 2012
Diamond Proposal Number(s): 7141

Abstract: The SAC (spindle assembly checkpoint) is a surveillance system that ensures the timely and accurate transmission of the genetic material to offspring. The process implies kinetochore targeting of the mitotic kinases Bub1 (budding uninhibited by benzamidine 1), BubR1 (Bub1 related) and Mps1 (monopolar spindle 1), which is mediated by the N-terminus of each kinase. In the present study we report the 1.8 Å (1 Å=0.1 nm) crystal structure of the TPR (tetratricopeptide repeat) domain in the N-terminal region of human Mps1. The structure reveals an overall high similarity to the TPR motif of the mitotic checkpoint kinases Bub1 and BubR1, and a number of unique features that include the absence of the binding site for the kinetochore structural component KNL1 (kinetochore-null 1; blinkin), and determinants of dimerization. Moreover, we show that a stretch of amino acids at the very N-terminus of Mps1 is required for dimer formation, and that interfering with dimerization results in mislocalization and misregulation of kinase activity. The results of the present study provide an important insight into the molecular details of the mitotic functions of Mps1 including features that dictate substrate selectivity and kinetochore docking.

Journal Keywords: Vesicular; Amino; Cell; Crystallography; X-Ray; HEK293; HeLa; Heterotrimeric; Humans; M; Protein; Tertiary; Protein-Serine-Threonine; Protein-Tyrosine; Repetitive; Amino Acid

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: No

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