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Cited by 47Glycogen Storage Diseases and MyoclonusMetabolism, Diabetes, and CancerEnzyme Structure and Function

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Mechanism of glycogen synthase inactivation and interaction with glycogenin

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Marr, Laura, Biswas, Dipsikha, Daly, Leonard A., Browning, Christopher, Vial, Sarah C. M., Maskell, Daniel P., Hudson, Catherine, Bertrand, Jay A., Pollard, John, Ranson, Neil A., Khatter, Heena, Eyers, Claire E., Sakamoto, Kei, Zeqiraj, Elton·2022·Nature Communications
DOI 10.1038/s41467-022-31109-6PMC PMC9188544

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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.

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Metadata

Authors
Marr, L., Biswas, D., Daly, L. A., Browning, C., Vial, S. C. M., Maskell, D. P., Hudson, C., Bertrand, J. A., Pollard, J., Ranson, N. A., Khatter, H., Eyers, C. E., Sakamoto, K., & Zeqiraj, E.
Affiliations
  • University of Leeds (GB)
  • University of Copenhagen (DK)
  • University of Liverpool (GB)
  • Vertex Pharmaceuticals (United Kingdom) (GB)
Corresponding author
Zeqiraj, Elton
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-06-11
Volume
13
Issue
1
Pages
3372-3372
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-31109-6
PMC
PMC9188544
OpenAlex
W4282932643
Cited by
47
References
3
Citations by year
2026: 8 · 2025: 15 · 2024: 14 · 2023: 9 · 2022: 1
FWCI
7.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • RCUK | Medical Research Council
  • Novo Nordisk Foundation (NNF) Center for Basic Metabolic Research
  • RCUK | Biotechnology and Biological Sciences Research Council (BB/S018514/1, BB/M012557/1, BB/R000182/1)
  • Wellcome Trust (108466/Z/15/Z, 221524/Z/20/Z, 200523/Z/16/Z)
  • Royal Society (RG170407)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Glycogen Storage Diseases and Myoclonus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
glycogen synthase, glycogenin, glycogen phosphorylation, cryo-EM structure, protein phosphorylation
MeSH terms
Glucosyltransferases, Glycogen, Glycogen Synthase, Glycoproteins, Humans, Phosphorylation, Muscle, Skeletal, Glucose-6-Phosphate

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