7ZBN

Cryo-EM structure of the human GS-GN complex in the inhibited state

Summary for 7ZBN

• Entry DOI: 10.2210/pdb7zbn/pdb
• EMDB information: 14587
• Descriptor: Glycogen [starch] synthase, muscle, Isoform GN-1 of Glycogenin-1 (3 entities in total)
• Functional Keywords: glycosyltransferase, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 485579.06

Authors

Marr, L.,Zeqiraj, E. (deposition date: 2022-03-23, release date: 2022-06-22, Last modification date: 2024-11-20)

Primary citation

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.
Mechanism of glycogen synthase inactivation and interaction with glycogenin.
Nat Commun, 13:3372-3372, 2022

PubMed 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.

PubMed: 35690592
DOI: 10.1038/s41467-022-31109-6

Experimental method

ELECTRON MICROSCOPY (2.62 Å)