Mechanism of glycogen synthase inactivation and interaction with glycogenin

Laura Marr, Dipsikha Biswas, Leonard A. Daly, Christopher Browning, Sarah C. M. Vial, Daniel P. Maskell, Catherine Hudson, Jay A. Bertrand, John Pollard, Neil A. Ranson, Heena Khatter, Claire E. Eyers, Kei Sakamoto and Elton Zeqiraj ()
Additional contact information
Laura Marr: University of Leeds
Dipsikha Biswas: Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
Leonard A. Daly: University of Liverpool
Christopher Browning: Vertex Pharmaceuticals (Europe) Limited, Milton Park
Sarah C. M. Vial: Vertex Pharmaceuticals (Europe) Limited, Milton Park
Daniel P. Maskell: University of Leeds
Catherine Hudson: Vertex Pharmaceuticals (Europe) Limited, Milton Park
Jay A. Bertrand: Vertex Pharmaceuticals (Europe) Limited, Milton Park
John Pollard: Vertex Pharmaceuticals (Europe) Limited, Milton Park
Neil A. Ranson: University of Leeds
Heena Khatter: Vertex Pharmaceuticals (Europe) Limited, Milton Park
Claire E. Eyers: University of Liverpool
Kei Sakamoto: Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen
Elton Zeqiraj: University of Leeds

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Glycogen is the major glucose reserve in eukaryotes, and defects in glycogen metabolism and structure lead to disease. Glycogenesis involves interaction of glycogenin (GN) with glycogen synthase (GS), where GS is activated by glucose-6-phosphate (G6P) and inactivated by phosphorylation. We describe the 2.6 Å resolution cryo-EM structure of phosphorylated human GS revealing an autoinhibited GS tetramer flanked by two GN dimers. Phosphorylated N- and C-termini from two GS protomers converge near the G6P-binding pocket and buttress against GS regulatory helices. This keeps GS in an inactive conformation mediated by phospho-Ser641 interactions with a composite “arginine cradle”. Structure-guided mutagenesis perturbing interactions with phosphorylated tails led to increased basal/unstimulated GS activity. We propose that multivalent phosphorylation supports GS autoinhibition through interactions from a dynamic “spike” region, allowing a tuneable rheostat for regulating GS activity. This work therefore provides insights into glycogen synthesis regulation and facilitates studies of glycogen-related diseases.

Date: 2022
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DOI: 10.1038/s41467-022-31109-6

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