Differential Binding Partners of the Mis18α/β YIPPEE Domains Regulate Mis18 Complex Recruitment to Centromeres

•Centromere recruitment requires the CENP-C interaction domains of Mis18BP1 and Mis18β•Mis18α and Mis18β have evolved to direct different functions within the Mis18 complex•The YIPPEE domain of Mis18α directly binds to Mis18BP1•Mis18β directly interacts with the C terminus of CENP-C via its YIPPEE domain

SummaryThe Mis18 complex specifies the site of new CENP-A nucleosome assembly by recruiting the CENP-A-specific assembly factor HJURP (Holliday junction recognition protein). The human Mis18 complex consists of Mis18α, Mis18β, and Mis18 binding protein 1 (Mis18BP1/hsKNL2). Although Mis18α and Mis18β are highly homologous proteins, we find that their conserved YIPPEE domains mediate distinct interactions that are essential to link new CENP-A deposition to existing centromeres. We find that Mis18α directly interacts with the N terminus of Mis18BP1, whereas Mis18β directly interacts with CENP-C during G1 phase, revealing that these proteins have evolved to serve distinct functions in centromeres of higher eukaryotes. The N terminus of Mis18BP1, containing both the Mis18α and CENP-C binding domains, is necessary and sufficient for centromeric localization. Therefore, the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition.

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