Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion

Kodai Hara; Ge Zheng; Qianhui Qu; Hong Liu; Zhuqing Ouyang; Zhe Chen; Diana R Tomchick; Hongtao Yu

doi:10.1038/nsmb.2880

Structure of cohesin subcomplex pinpoints direct shugoshin-Wapl antagonism in centromeric cohesion

Nat Struct Mol Biol. 2014 Oct;21(10):864-70. doi: 10.1038/nsmb.2880. Epub 2014 Aug 31.

Authors

Kodai Hara¹, Ge Zheng², Qianhui Qu³, Hong Liu⁴, Zhuqing Ouyang³, Zhe Chen⁵, Diana R Tomchick⁵, Hongtao Yu⁴

Affiliations

¹ 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] [3].
² 1] Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2].
³ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
⁴ 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.
⁵ Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Binding Sites
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Cycle Proteins / antagonists & inhibitors
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Cell Cycle Proteins / ultrastructure*
Centromere / metabolism*
Chromatids / genetics*
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism
Chromosomal Proteins, Non-Histone / ultrastructure*
Chromosome Segregation / genetics*
Cohesins
Crystallography, X-Ray
DNA-Binding Proteins
HeLa Cells
Humans
Mitosis / genetics
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Nuclear Proteins / ultrastructure
Phosphoproteins / ultrastructure
Phosphorylation
Protein Binding
Protein Phosphatase 2 / genetics
Protein Structure, Tertiary
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
RNA Interference
RNA, Small Interfering

Substances

Adaptor Proteins, Signal Transducing
CDCA5 protein, human
Carrier Proteins
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Nuclear Proteins
Phosphoproteins
Proto-Oncogene Proteins
RAD21 protein, human
RNA, Small Interfering
SGO1 protein, human
WAPL protein, human
Protein Phosphatase 2

Grants and funding

HHMI/Howard Hughes Medical Institute/United States