title: Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion.
abstract: Orderly termination of sister-chromatid cohesion during mitosis is critical for accurate chromosome segregation. During prophase, mitotic kinases phosphorylate cohesin and its protector sororin, triggering Wapl-dependent cohesin release from chromosome arms. The shugoshin (Sgo1)-PP2A complex protects centromeric cohesin until its cleavage by separase at anaphase onset. Here, we report the crystal structure of a human cohesin subcomplex comprising SA2 and Scc1. Multiple HEAT repeats of SA2 form a dragon-shaped structure. Scc1 makes extensive contacts with SA2, with one binding hotspot. Sgo1 and Wapl compete for binding to a conserved site on SA2-Scc1. At this site, mutations of SA2 residues that disrupt Wapl binding bypass the Sgo1 requirement in cohesion protection. Thus, in addition to recruiting PP2A to dephosphorylate cohesin and sororin, Sgo1 physically shields cohesin from Wapl. This unexpected, direct antagonism between Sgo1 and Wapl augments centromeric cohesion protection.
authors.affiliation: 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] [3].
authors.forename: Kodai
authors.initials: K
authors.lastname: Hara
authors.affiliation: 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
authors.forename: Ge
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Qianhui
authors.initials: Q
authors.lastname: Qu
authors.affiliation: 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Ouyang
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.affiliation: 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure*; D002503:Centromere / Q000378:metabolism*; D002842:Chromatids / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D020090:Chromosome Segregation / Q000235:genetics*; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D010750:Phosphoproteins / Q000648:ultrastructure; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000235:genetics; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000097722:Cohesins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D054648:Protein Phosphatase 2; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097722:Cohesins; C500695:CDCA5 protein, human; C429022:RAD21 protein, human; C496644:SGO1 protein, human; C488092:WAPL protein, human