title: Shugoshin is a Mad1/Cdc20-like interactor of Mad2.
abstract: Mammalian centromeric cohesin is protected from phosphorylation-dependent displacement in mitotic prophase by shugoshin-1 (Sgo1), while shugoshin-2 (Sgo2) protects cohesin from separase-dependent cleavage in meiosis I. In higher eukaryotes, progression and faithful execution of both mitosis and meiosis are controlled by the spindle assembly checkpoint, which delays anaphase onset until chromosomes have achieved proper attachment to microtubules. According to the so-called template model, Mad1-Mad2 complexes at unattached kinetochores instruct conformational change of soluble Mad2, thus catalysing Mad2 binding to its target Cdc20. Here, we show that human Sgo2, but not Sgo1, specifically interacts with Mad2 in a manner that strongly resembles the interactions of Mad2 with Mad1 or Cdc20. Sgo2 contains a Mad1/Cdc20-like Mad2-interaction motif and competes with Mad1 and Cdc20 for binding to Mad2. NMR and biochemical analyses show that shugoshin binding induces similar conformational changes in Mad2 as do Mad1 or Cdc20. Mad2 binding regulates fine-tuning of Sgo2's sub-centromeric localization. Mad2 binding is conserved in the only known Xenopus laevis shugoshin homologue and, compatible with a putative meiotic function, the interaction occurs in oocytes.
authors.affiliation: Department of Genetics, University of Bayreuth, Bayreuth, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Orth
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
authors.forename: Kinga
authors.initials: K
authors.lastname: Rehm
authors.forename: Ulli
authors.initials: U
authors.lastname: Rothweiler
authors.forename: Doris
authors.initials: D
authors.lastname: Heidmann
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Olaf
authors.initials: O
authors.lastname: Stemmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002503:Centromere / Q000502:physiology; D005260:Female; D006801:Humans; D018386:Kinetochores / Q000502:physiology; D064246:Mad2 Proteins; D008540:Meiosis / Q000502:physiology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D011487:Protein Conformation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D008941:Spindle Apparatus; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C496644:SGO1 protein, human; C510590:SGO2 protein, human; C577488:CDC20 protein, human