Human monocarboxylate transporters accept and relay protons via the bound substrate for selectivity and activity at physiological pH.

ABSTRACT: Human monocarboxylate/H⁺ transporters, MCT, facilitate the transmembrane translocation of vital weak acid metabolites, mainly l-lactate. Tumors exhibiting a Warburg effect rely on MCT activity for l-lactate release. Recently, high-resolution MCT structures revealed binding sites for anticancer drug candidates and the substrate. Three charged residues, Lys 38, Asp 309, and Arg 313 (MCT1 numbering) are essential for substrate binding and initiation of the alternating access conformational change. However, the mechanism by which the proton cosubstrate binds and traverses MCTs remained elusive. Here, we report that substitution of Lys 38 by neutral residues maintained MCT functionality in principle, yet required strongly acidic pH conditions for wildtype-like transport velocity. We

SUBMITTER: Geistlinger K 

PROVIDER: S-EPMC9982067 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature