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A highly conserved binding pocket on PP2A-B56 is required for shugoshin binding and cohesion protection

By Yumi Ueki, Michael Hadders, Melanie B Weisser, Isha Nasa, Tanmay Gupta, Emil T Hertz, Thomas Kruse, Guillermo Montoya, A. Arockia Jeyaprakash, Arminja N. Kettenbach, Susanne M.A. Lens, Jakob Nilsson

Posted 19 Dec 2020
bioRxiv DOI: 10.1101/2020.12.18.423432

The shugoshin proteins are universal protectors of centromeric cohesin during mitosis and meiosis. The binding of human Sgo1 to the PP2A-B56 phosphatase through a coiled coil (CC) region is believed to mediate cohesion protection during mitosis. Here we undertook a structure function analysis of the PP2A-B56-Sgo1 complex, revealing unanticipated aspects of complex formation and function. We establish that a highly conserved pocket of the B56 regulatory subunit is required for Sgo1 binding and cohesion protection. Consistent with this, we show that Sgo1 blocks the binding of PP2A-B56 substrates containing a canonical B56 binding motif. Surprisingly, we identify B56 and Sgo1 mutants that prevent complex formation yet support cohesion protection and normal mitotic progression. This suggests that Sgo1 and PP2A-B56 have cohesion protection activity independently of complex formation. Collectively our work provides important insight into cohesion protection during mitosis.

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