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Centromere localization and function of Mis18 requires Yippee-like domain-mediated oligomerization

DOI: 10.15252/embr.201541520 DOI Help

Authors: L. Subramanian (University of Edinburgh) , B. Medina - Pritchard (University of Edinburgh) , R. Barton (University of Edinburgh) , F. Spiller (University of Edinburgh) , R. Kulasegaran-shylini (University of Edinburgh) , G. Radaviciute (University of Edinburgh) , R. C. Allshire (University of Edinburgh) , A. Arockia Jeyaprakash (University of Edinburgh)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Embo Reports , VOL 17 (3) , PAGES 279 - 469

State: Published (Approved)
Published: February 2016
Diamond Proposal Number(s): 7613

Open Access Open Access

Abstract: Mis18 is a key regulator responsible for the centromere localization of the CENP‐A chaperone Scm3 in Schizosaccharomyces pombe and HJURP in humans, which establishes CENP‐A chromatin that defines centromeres. The molecular and structural determinants of Mis18 centromere targeting remain elusive. Here, by combining structural, biochemical, and yeast genetic studies, we show that the oligomerization of S. pombe Mis18, mediated via its conserved N‐terminal Yippee‐like domain, is crucial for its centromere localization and function. The crystal structure of the N‐terminal Yippee‐like domain reveals a fold containing a cradle‐shaped pocket that is implicated in protein/nucleic acid binding, which we show is required for Mis18 function. While the N‐terminal Yippee‐like domain forms a homodimer in vitro and in vivo, full‐length Mis18, including the C‐terminal α‐helical domain, forms a homotetramer in vitro. We also show that the Yippee‐like domains of human Mis18α/Mis18β interact to form a heterodimer, implying a conserved structural theme for Mis18 regulation.

Journal Keywords: CENP‐A; centromere; epigenetics; Mis18; Yippee

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography