Mechanism of glycogen synthase inactivation and interaction with glycogenin
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Mechanism of glycogen synthase inactivation and interaction with glycogenin. / 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.
In: Nature Communications, Vol. 13, No. 1, 3372, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Mechanism of glycogen synthase inactivation and interaction with glycogenin
AU - Marr, Laura
AU - Biswas, Dipsikha
AU - Daly, Leonard A.
AU - Browning, Christopher
AU - Vial, Sarah C.M.
AU - Maskell, Daniel P.
AU - Hudson, Catherine
AU - Bertrand, Jay A.
AU - Pollard, John
AU - Ranson, Neil A.
AU - Khatter, Heena
AU - Eyers, Claire E.
AU - Sakamoto, Kei
AU - Zeqiraj, Elton
N1 - Publisher Copyright: © 2022, The Author(s).
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-022-31109-6
DO - 10.1038/s41467-022-31109-6
M3 - Journal article
C2 - 35690592
AN - SCOPUS:85131796129
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3372
ER -
ID: 310965370