Mechanism of glycogen synthase inactivation and interaction with glycogenin

Research output: Contribution to journal › Journal article › Research › peer-review

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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

Harvard

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 2022, 'Mechanism of glycogen synthase inactivation and interaction with glycogenin', Nature Communications, vol. 13, no. 1, 3372. https://doi.org/10.1038/s41467-022-31109-6

APA

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. (2022). Mechanism of glycogen synthase inactivation and interaction with glycogenin. Nature Communications, 13(1), [3372]. https://doi.org/10.1038/s41467-022-31109-6

Vancouver

Marr L, Biswas D, Daly LA, Browning C, Vial SCM, Maskell DP et al. Mechanism of glycogen synthase inactivation and interaction with glycogenin. Nature Communications. 2022;13(1). 3372. https://doi.org/10.1038/s41467-022-31109-6

Author

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. / Mechanism of glycogen synthase inactivation and interaction with glycogenin. In: Nature Communications. 2022 ; Vol. 13, No. 1.

Bibtex

@article{962c84c408c644368f42a8a1df52fd18,
title = "Mechanism of glycogen synthase inactivation and interaction with glycogenin",
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 {\AA} 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.",
author = "Laura Marr and Dipsikha Biswas and Daly, {Leonard A.} and Christopher Browning and Vial, {Sarah C.M.} and Maskell, {Daniel P.} and Catherine Hudson and Bertrand, {Jay A.} and John Pollard and Ranson, {Neil A.} and Heena Khatter and Eyers, {Claire E.} and Kei Sakamoto and Elton Zeqiraj",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
doi = "10.1038/s41467-022-31109-6",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

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