title: Centromere localization and function of Mis18 requires Yippee-like domain-mediated oligomerization.
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.
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Lakxmi
authors.initials: L
authors.lastname: Subramanian
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Bethan
authors.initials: B
authors.lastname: Medina-Pritchard
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Barton
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Spiller
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Raghavendran
authors.initials: R
authors.lastname: Kulasegaran-Shylini
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Guoda
authors.initials: G
authors.lastname: Radaviciute
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK.
authors.forename: Robin C
authors.initials: RC
authors.lastname: Allshire
authors.affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh, UK jeyaprakash.arulanandam@ed.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Arockia Jeyaprakash
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002503:Centromere / Q000235:genetics / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D055503:Protein Multimerization; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; C410349:Cnp1 protein, S pombe; D004268:DNA-Binding Proteins; C539323:Mis18 protein, S pombe; D018832:Molecular Chaperones; D029702:Schizosaccharomyces pombe Proteins
keywords: CENP‐A; Mis18; Yippee; centromere; epigenetics