7zbn

From Proteopedia

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

Structural highlights

7zbn is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.62Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GYS1_HUMAN Glycogen storage disease due to muscle and heart glycogen synthase deficiency. The disease is caused by variants affecting the gene represented in this entry.

Function

GYS1_HUMAN Glycogen synthase participates in the glycogen biosynthetic process along with glycogenin and glycogen branching enzyme. Extends the primer composed of a few glucose units formed by glycogenin by adding new glucose units to it. In this context, glycogen synthase transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.^[1]

Publication Abstract from PubMed

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 A 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.

Mechanism of glycogen synthase inactivation and interaction with glycogenin.,Marr L, Biswas D, Daly LA, Browning C, Vial SCM, Maskell DP, Hudson C, Bertrand JA, Pollard J, Ranson NA, Khatter H, Eyers CE, Sakamoto K, Zeqiraj E Nat Commun. 2022 Jun 11;13(1):3372. doi: 10.1038/s41467-022-31109-6. PMID:35690592^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ McCorvie TJ, Loria PM, Tu M, Han S, Shrestha L, Froese DS, Ferreira IM, Berg AP, Yue WW. Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate. Nat Struct Mol Biol. 2022 Jul;29(7):628-638. doi: 10.1038/s41594-022-00799-3., Epub 2022 Jul 14. PMID:35835870 doi:http://dx.doi.org/10.1038/s41594-022-00799-3
↑ Marr L, Biswas D, Daly LA, Browning C, Vial SCM, Maskell DP, Hudson C, Bertrand JA, Pollard J, Ranson NA, Khatter H, Eyers CE, Sakamoto K, Zeqiraj E. Mechanism of glycogen synthase inactivation and interaction with glycogenin. Nat Commun. 2022 Jun 11;13(1):3372. PMID:35690592 doi:10.1038/s41467-022-31109-6