Evolutionary analysis reveals the origin of sodium coupling in glutamate transporters

Reddy, Krishna D, Rasool, Burha, Akher, Farideh Badichi, Kutlešić, Nemanja, Pant, Swati, Boudker, Olga (August 2025) Evolutionary analysis reveals the origin of sodium coupling in glutamate transporters. Nature Structural & Molecular Biology. ISSN 1545-9993

PDF 10.1038.s41594-025-01652-z.pdf - Published Version Available under License Creative Commons Attribution Non-commercial. Download (8MB)

Abstract

Secondary active membrane transporters harness the energy of ion gradients to concentrate their substrates. Homologous transporters evolved to couple transport to different ions in response to changing environments and needs. The bases of such diversification and, thus, principles of ion coupling are unexplored. Here, using phylogenetics and ancestral protein reconstruction, we investigated sodium-coupled transport in prokaryotic glutamate transporters, a mechanism ubiquitous across life domains and critical to neurotransmitter recycling in humans by excitatory amino acid transporters from the solute carrier 1 family. By inferring ancestral prokaryotic transporter sequences during a change in the ion-coupling mechanism, we found an evolutionary transition from sodium-dependent to independent substrate binding and transport. Structural and functional experiments on ancestral transporters suggest that the transition involved allosteric mutations, rendering sodium binding dispensable without affecting the ion-binding sites. Allosteric tuning of transporters' energy landscapes might be a widespread route of their functional diversification.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > small molecules > Glutamate bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > small molecules
CSHL Authors:	Kutlesic, Nemanja
Communities:	CSHL labs > Lukey lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	25 August 2025
Date Deposited:	02 Sep 2025 14:58
Last Modified:	02 Sep 2025 14:58
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41952

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