Biology of Human Sodium Glucose Transporters

Wright, Ernest M.; Loo, Donald D. F.; Hirayama, Bruce A.

doi:10.1152/physrev.00055.2009

Cited by 1,210 publications

(1,387 citation statements)

References 249 publications

(494 reference statements)

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“…Ions and substrates are bound near the middle of the membrane stabilized by electrostatic interactions with unwound regions of transmembrane helix (TM) 1 and often TM6 (4). The recurrence of this fold in transporters that play critical roles in fundamental physiological processes (5,6) has spurred intense interest in defining the principles of alternating access.…”

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confidence: 99%

Conformational cycle and ion-coupling mechanism of the Na ⁺ /hydantoin transporter Mhp1

Kazmier

Sharma

Islam

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

147

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Ion-dependent transporters of the LeuT-fold couple the uptake of physiologically essential molecules to transmembrane ion gradients. Defined by a conserved 5-helix inverted repeat that encodes common principles of ion and substrate binding, the LeuTfold has been captured in outward-facing, occluded, and inwardfacing conformations. However, fundamental questions relating to the structural basis of alternating access and coupling to ion gradients remain unanswered. Here, we used distance measurements between pairs of spin labels to define the conformational cycle of the Na + -coupled hydantoin symporter Mhp1 from Microbacterium liquefaciens. Our results reveal that the inward-facing and outward-facing Mhp1 crystal structures represent sampled intermediate states in solution. Here, we provide a mechanistic context for these structures, mapping them into a model of transport based on ion-and substrate-dependent conformational equilibria. In contrast to the Na + /leucine transporter LeuT, our results suggest that Na + binding at the conserved second Na + binding site does not change the energetics of the inward-and outward-facing conformations of Mhp1. Comparative analysis of ligand-dependent alternating access in LeuT and Mhp1 lead us to propose that different coupling schemes to ion gradients may define distinct conformational mechanisms within the LeuT-fold class.EPR | DEER | Na + -coupled symport | conformational dynamics | transport mechanism

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mentioning

confidence: 99%

Conformational cycle and ion-coupling mechanism of the Na ⁺ /hydantoin transporter Mhp1

Kazmier

Sharma

Islam

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

147

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“…1A). Although the binding order and partial reaction steps corresponding to Na + and sugar binding to the extracellular face are well understood for hSGLT1 (3) and vSGLT (4,5), less is known about substrate release to the cytoplasm, i.e., symmetrical release (glucose off before Na + ), Na + before glucose, or random. Models of symmetrical release (Fig.…”

mentioning

confidence: 99%

Stochastic steps in secondary active sugar transport

Adelman

Ghezzi

Bisignano

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Secondary active transporters, such as those that adopt the leucinetransporter fold, are found in all domains of life, and they have the unique capability of harnessing the energy stored in ion gradients to accumulate small molecules essential for life as well as expel toxic and harmful compounds. How these proteins couple ion binding and transport to the concomitant flow of substrates is a fundamental structural and biophysical question that is beginning to be answered at the atomistic level with the advent of high-resolution structures of transporters in different structural states. Nonetheless, the dynamic character of the transporters, such as ion/substrate binding order and how binding triggers conformational change, is not revealed from static structures, yet it is critical to understanding their function. Here, we report a series of molecular simulations carried out on the sugar transporter vSGLT that lend insight into how substrate and ions are released from the inward-facing state of the transporter. Our simulations reveal that the order of release is stochastic. Functional experiments were designed to test this prediction on the human homolog, hSGLT1, and we also found that cytoplasmic release is not ordered, but we confirmed that substrate and ion binding from the extracellular space is ordered. Our findings unify conflicting published results concerning cytoplasmic release of ions and substrate and hint at the possibility that other transporters in the superfamily may lack coordination between ions and substrate in the inward-facing state.T ransport of sugar molecules across membranes is virtually ubiquitous in biology, and it is of central importance in human health. The uptake of glucose is especially crucial due to its pivotal role in cellular metabolism and energy production. In mammals, glucose is absorbed in the small intestine and kidney via sodium-dependent glucose transporters (SGLTs), which localize to the apical membrane and concentrate glucose in the epithelia. SGLTs fall into the large leucine-transporter (LeuT) structural family of secondary active transporters that have evolved to concentrate a wide array of substrates across membranes using the energy stored in the Na + electrochemical potential gradient. For symporters in this family, transport occurs by an alternating access mechanism (1) in which the transporter first binds ligands in an outward-facing conformation, and then transitions to an inwardfacing conformation that releases the cargo to the cytoplasm. The order of ion and substrate binding and unbinding is likely tied to the function of the transporter, making it possible to convert the energy stored in the ion gradient into a substrate gradient, and vice versa when these proteins operate in reverse.Extensive biochemical uptake assays and electrophysiological studies of SGLTs have led to a view of Na + /glucose cotransport in which Na + binding precedes sugar binding on the external face of the transporter. Kinetic models adhering to this mechanism satisfactorily account fo...

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“…In mammals, glucose is transported across the cell membrane by transporters, which belong to one of two families: the glucose transporters (SLC2 or GLUT gene family) (Augustin, 2010;Wilson-O'Brien et al, 2010;Mueckler and Thorens, 2013) and the sodium-coupled glucose transporters (SGLT or SLC5 gene family) (Wright et al, 2011;Wright, 2013). Members of the SGLT are expressed in the kidney and intestine where they actively transport glucose and allow reabsorption against a concentration gradient (Wright et al, 2011;Wright, 2013). The SLC2 family members (or GLUT proteins) are facilitative transports and only move glucose in the direction of a concentration gradient (Augustin, 2010;Mueckler and Thorens, 2013).…”

Section: Mammalian Glucose Metabolismmentioning

confidence: 99%

Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

Irwin

2014

Molecular Phylogenetics and Evolution

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Glucose is an essential nutrient that must be distributed throughout the body to provide energy to sustain physiological functions. Glucose is delivered to distant tissues via be blood stream, and complex systems have evolved to maintain the levels of glucose within a narrow physiological range. Phosphorylation of glucose, by glucokinase, is an essential component of glucose homeostasis, both from the regulatory and metabolic point-of-view. Here we review the evolution of glucose utilization from the perspective of glucokinase. We discuss the origin of glucokinase, its evolution within the hexokinase gene family, and the evolution of its interacting regulatory partner, glucokinase regulatory protein (GCKR). Evolution of the structure and sequence of both glucokinase and GCKR have been necessary to optimize glucokinase in its role in glucose metabolism.

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Biology of Human Sodium Glucose Transporters

Cited by 1,210 publications

References 249 publications

Conformational cycle and ion-coupling mechanism of the Na ⁺ /hydantoin transporter Mhp1

Conformational cycle and ion-coupling mechanism of the Na ⁺ /hydantoin transporter Mhp1

Stochastic steps in secondary active sugar transport

Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

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Biology of Human Sodium Glucose Transporters

Cited by 1,210 publications

References 249 publications

Conformational cycle and ion-coupling mechanism of the Na + /hydantoin transporter Mhp1

Conformational cycle and ion-coupling mechanism of the Na + /hydantoin transporter Mhp1

Stochastic steps in secondary active sugar transport

Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

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Conformational cycle and ion-coupling mechanism of the Na ⁺ /hydantoin transporter Mhp1

Conformational cycle and ion-coupling mechanism of the Na ⁺ /hydantoin transporter Mhp1