A highly conserved pocket on PP2A-B56 is required for hSgo1 binding and cohesion protection during mitosis
Ueki, Yumi; Hadders, Michael A.; Weisser, Melanie B.; Nasa, Isha; Sotelo-Parrilla, Paula; Cressey, Lauren E.; Gupta, Tanmay; Hertz, Emil P. T.; Kruse, Thomas; Montoya, Guillermo; Jeyaprakash, A. Arockia; Kettenbach, Arminja; Lens, Susanne M. A.; Nilsson, Jakob
(2021) EMBO Reports, volume 22, issue 7, pp. 1 - 13
(Article)
Abstract
The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human hSgo1 to the PP2A-B56 phosphatase through a coiled-coil (CC) region mediates cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A-B56-hSgo1 complex, revealing unanticipated aspects of complex formation and
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function. We establish that a highly conserved pocket on the B56 regulatory subunit is required for hSgo1 binding and cohesion protection during mitosis in human somatic cells. Consistent with this, we show that hSgo1 blocks the binding of PP2A-B56 substrates containing a canonical B56 binding motif. We find that PP2A-B56 bound to hSgo1 dephosphorylates Cdk1 sites on hSgo1 itself to modulate cohesin interactions. Collectively our work provides important insight into cohesion protection during mitosis.
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Keywords: B56, PP2A‐, cohesin, mitosis, phosphatase, shugoshin, PP2A-B56, Genetics, Molecular Biology, Biochemistry
ISSN: 1469-221X
Publisher: Nature Publishing Group
Note: Funding Information: Work at the Novo Nordisk Foundation Center for Protein Research is supported by grant NNF14CC0001 and JNI is supported by grants from the Danish Cancer Society (R167- A10951-17-S2), Independent Research Fund Denmark (8021-00101B), and Novo Nordisk Foundation (NNF18OC0053124). This work was also supported by the cryo-EM (NNF0024386) and cryoNET (NNF17SA0030214) grants to G.M. G.M. is a member of the Integrative Structural Biology Cluster (ISBUC) at the University of Copenhagen. M.W. was supported by the Swiss National Fund (P2EZP3_178624) and the Danish Lundbeckfonden (2017-3212). ANK was supported by grants from NIH/NIGMS (R35GM119455). The Orbitrap Fusion Tribrid mass spectrometer was acquired with support from NIH (S10-OD016212). MH and SMAL are part of the Oncode Institute, which is partly financed by the Dutch Cancer Society and work for this project was funded by a grant from the Dutch Cancer Society (KWF research project 10366). AAJ acknowledges the Wellcome Trust for their support through the Research Career Development (095822) and Senior Research Fellowship (202811) awards. TG acknowledges the Darwin Trust of Edinburgh for the studentship. We thank Hongtao Yu for providing Sgo1 antibody and Sally Wheatley for providing the Borealin antibody. We thank Adele Marston for comments on the manuscript and fruitful discussions. We thank the protein production facility at NNF CPR for help with producing recombinant BubR1. Funding Information: Work at the Novo Nordisk Foundation Center for Protein Research is supported by grant NNF14CC0001 and JNI is supported by grants from the Danish Cancer Society (R167‐ A10951‐17‐S2), Independent Research Fund Denmark (8021‐00101B), and Novo Nordisk Foundation (NNF18OC0053124). This work was also supported by the cryo‐EM (NNF0024386) and cryoNET (NNF17SA0030214) grants to G.M. G.M. is a member of the Integrative Structural Biology Cluster (ISBUC) at the University of Copenhagen. M.W. was supported by the Swiss National Fund (P2EZP3_178624) and the Danish Lundbeckfonden (2017‐3212). ANK was supported by grants from NIH/NIGMS (R35GM119455). The Orbitrap Fusion Tribrid mass spectrometer was acquired with support from NIH (S10‐OD016212). MH and SMAL are part of the Oncode Institute, which is partly financed by the Dutch Cancer Society and work for this project was funded by a grant from the Dutch Cancer Society (KWF research project 10366). AAJ acknowledges the Wellcome Trust for their support through the Research Career Development (095822) and Senior Research Fellowship (202811) awards. TG acknowledges the Darwin Trust of Edinburgh for the studentship. We thank Hongtao Yu for providing Sgo1 antibody and Sally Wheatley for providing the Borealin antibody. We thank Adele Marston for comments on the manuscript and fruitful discussions. We thank the protein production facility at NNF CPR for help with producing recombinant BubR1. Publisher Copyright: © 2021 The Authors
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