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Basilico, Federica; Maffini, Stefano; Weir, John R.; Prumbaum, Daniel; Rojas, Ana M.; Zimniak, Tomasz; De Antoni, Anna; Jeganathan, Sadasivam; Voss, Beate; Gerwen, Suzan van; Krenn, Veronica; Massimiliano, Lucia; Valencia, Alfonso; Vetter, Ingrid R.; Herzog, Franz; Raunser, Stefan; Pasqualato, Sebastiano; Musacchio, Andrea (2014): The pseudo GTPase CENP-M drives human kinetochore assembly. In: eLife, Vol. 3, e02978
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Abstract

Kinetochores, multi-subunit complexes that assemble at the interface with centromeres, bind spindle microtubules to ensure faithful delivery of chromosomes during cell division. The configuration and function of the kinetochore-centromere interface is poorly understood. We report that a protein at this interface, CENP-M, is structurally and evolutionarily related to small GTPases but is incapable of GTP-binding and conformational switching. We show that CENP-M is crucially required for the assembly and stability of a tetramer also comprising CENP-I, CENP-H, and CENP-K, the HIKM complex, which we extensively characterize through a combination of structural, biochemical, and cell biological approaches. A point mutant affecting the CENP-M/CENP-I interaction hampers kinetochore assembly and chromosome alignment and prevents kinetochore recruitment of the CENP-T/W complex, questioning a role of CENP-T/W as founder of an independent axis of kinetochore assembly. Our studies identify a single pathway having CENP-C as founder, and CENP-H/I/K/M and CENP-T/W as CENP-C-dependent followers.