Molecular architecture of the glycogen- committed PP1/PTG holoenzyme

Marta Stefania Semrau, Gabriele Giachin, Sonia Covaceuszach, Alberto Cassetta, Nicola Demitri, Paola Storici () and Graziano Lolli ()
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Marta Stefania Semrau: University of Trento
Gabriele Giachin: University of Padua
Sonia Covaceuszach: Institute of Crystallography - C.N.R.- Trieste Outstation
Alberto Cassetta: Institute of Crystallography - C.N.R.- Trieste Outstation
Nicola Demitri: XRD2 Beamline, Elettra Sincrotrone Trieste S.C.p.A
Paola Storici: Protein Facility, Elettra Sincrotrone Trieste S.C.p.A
Graziano Lolli: University of Trento

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract The delicate alternation between glycogen synthesis and degradation is governed by the interplay between key regulatory enzymes altering the activity of glycogen synthase and phosphorylase. Among these, the PP1 phosphatase promotes glycogenesis while inhibiting glycogenolysis. PP1 is, however, a master regulator of a variety of cellular processes, being conveniently directed to each of them by scaffolding subunits. PTG, Protein Targeting to Glycogen, addresses PP1 action to glycogen granules. In Lafora disease, the most aggressive pediatric epilepsy, genetic alterations leading to PTG accumulation cause the deposition of insoluble polyglucosans in neurons. Here, we report the crystallographic structure of the ternary complex PP1/PTG/carbohydrate. We further refine the mechanism of the PTG-mediated PP1 recruitment to glycogen by identifying i) an unusual combination of recruitment sites, ii) their contributions to the overall binding affinity, and iii) the conformational heterogeneity of this complex by in solution SAXS analyses.

Date: 2022
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DOI: 10.1038/s41467-022-33693-z

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