Marr, Laura, Biswas, Dipsikha, Daly, Leonard A 
ORCID: 0000-0001-9712-9676, Browning, Christopher, Vial, Sarah CM, Maskell, Daniel P, Hudson, Catherine, Bertrand, Jay A, Pollard, John, Ranson, Neil A et al (show 4 more authors)
(2022)
Mechanism of glycogen synthase inactivation and interaction with glycogenin.
NATURE COMMUNICATIONS, 13 (1).
3372-.
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Marr et al. Nature Comms 2022.pdf - Published version Download (2MB) | Preview |
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Muscle, Skeletal, Humans, Glycogen, Glucosyltransferases, Glycogen Synthase, Glycoproteins, Glucose-6-Phosphate, Phosphorylation |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 24 Jun 2022 10:26 |
| Last Modified: | 18 Jan 2023 20:57 |
| DOI: | 10.1038/s41467-022-31109-6 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3157110 |
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