Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.

Glucokinase (GCK) catalyzes the rate-limiting step of glucose catabolism in the pancreas, where it functions as the body's principal glucose sensor. GCK dysfunction leads to several potentially fatal diseases including maturity-onset diabetes of the young type II (MODY-II) and persistent hypogl...

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Autores principales:	Mioara Larion, Roberto Kopke Salinas, Lei Bruschweiler-Li, Brian G Miller, Rafael Brüschweiler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7100dd73a44140ac85fbfb0580fc0fd5
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spelling	oai:doaj.org-article:7100dd73a44140ac85fbfb0580fc0fd52021-11-18T05:37:19ZOrder-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.1544-91731545-788510.1371/journal.pbio.1001452https://doaj.org/article/7100dd73a44140ac85fbfb0580fc0fd52012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23271955/pdf/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Glucokinase (GCK) catalyzes the rate-limiting step of glucose catabolism in the pancreas, where it functions as the body's principal glucose sensor. GCK dysfunction leads to several potentially fatal diseases including maturity-onset diabetes of the young type II (MODY-II) and persistent hypoglycemic hyperinsulinemia of infancy (PHHI). GCK maintains glucose homeostasis by displaying a sigmoidal kinetic response to increasing blood glucose levels. This positive cooperativity is unique because the enzyme functions exclusively as a monomer and possesses only a single glucose binding site. Despite nearly a half century of research, the mechanistic basis for GCK's homotropic allostery remains unresolved. Here we explain GCK cooperativity in terms of large-scale, glucose-mediated disorder-order transitions using 17 isotopically labeled isoleucine methyl groups and three tryptophan side chains as sensitive nuclear magnetic resonance (NMR) probes. We find that the small domain of unliganded GCK is intrinsically disordered and samples a broad conformational ensemble. We also demonstrate that small-molecule diabetes therapeutic agents and hyperinsulinemia-associated GCK mutations share a strikingly similar activation mechanism, characterized by a population shift toward a more narrow, well-ordered ensemble resembling the glucose-bound conformation. Our results support a model in which GCK generates its cooperative kinetic response at low glucose concentrations by using a millisecond disorder-order cycle of the small domain as a "time-delay loop," which is bypassed at high glucose concentrations, providing a unique mechanism to allosterically regulate the activity of human GCK under physiological conditions.Mioara LarionRoberto Kopke SalinasLei Bruschweiler-LiBrian G MillerRafael BrüschweilerPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 10, Iss 12, p e1001452 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Mioara Larion Roberto Kopke Salinas Lei Bruschweiler-Li Brian G Miller Rafael Brüschweiler Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
description	Glucokinase (GCK) catalyzes the rate-limiting step of glucose catabolism in the pancreas, where it functions as the body's principal glucose sensor. GCK dysfunction leads to several potentially fatal diseases including maturity-onset diabetes of the young type II (MODY-II) and persistent hypoglycemic hyperinsulinemia of infancy (PHHI). GCK maintains glucose homeostasis by displaying a sigmoidal kinetic response to increasing blood glucose levels. This positive cooperativity is unique because the enzyme functions exclusively as a monomer and possesses only a single glucose binding site. Despite nearly a half century of research, the mechanistic basis for GCK's homotropic allostery remains unresolved. Here we explain GCK cooperativity in terms of large-scale, glucose-mediated disorder-order transitions using 17 isotopically labeled isoleucine methyl groups and three tryptophan side chains as sensitive nuclear magnetic resonance (NMR) probes. We find that the small domain of unliganded GCK is intrinsically disordered and samples a broad conformational ensemble. We also demonstrate that small-molecule diabetes therapeutic agents and hyperinsulinemia-associated GCK mutations share a strikingly similar activation mechanism, characterized by a population shift toward a more narrow, well-ordered ensemble resembling the glucose-bound conformation. Our results support a model in which GCK generates its cooperative kinetic response at low glucose concentrations by using a millisecond disorder-order cycle of the small domain as a "time-delay loop," which is bypassed at high glucose concentrations, providing a unique mechanism to allosterically regulate the activity of human GCK under physiological conditions.
format	article
author	Mioara Larion Roberto Kopke Salinas Lei Bruschweiler-Li Brian G Miller Rafael Brüschweiler
author_facet	Mioara Larion Roberto Kopke Salinas Lei Bruschweiler-Li Brian G Miller Rafael Brüschweiler
author_sort	Mioara Larion
title	Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
title_short	Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
title_full	Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
title_fullStr	Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
title_full_unstemmed	Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
title_sort	order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/7100dd73a44140ac85fbfb0580fc0fd5
work_keys_str_mv	AT mioaralarion orderdisordertransitionsgovernkineticcooperativityandallosteryofmonomerichumanglucokinase AT robertokopkesalinas orderdisordertransitionsgovernkineticcooperativityandallosteryofmonomerichumanglucokinase AT leibruschweilerli orderdisordertransitionsgovernkineticcooperativityandallosteryofmonomerichumanglucokinase AT briangmiller orderdisordertransitionsgovernkineticcooperativityandallosteryofmonomerichumanglucokinase AT rafaelbruschweiler orderdisordertransitionsgovernkineticcooperativityandallosteryofmonomerichumanglucokinase
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Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase.

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