Helix 8 and helix 10 are involved in substrate recognition in the rat monocarboxylate transporter MCT1.

Abstract:

:Transport of lactate, pyruvate, and the ketone bodies, acetoacetate and beta-hydroxybutyrate, is mediated in many mammalian cells by the monocarboxylate transporter MCT1. To be accepted as a substrate, a carboxyl group and an unpolar side chain are necessary. Site-directed mutagenesis of the rat MCT1 was used to identify residues which are involved in substrate recognition. Helices 8 and 10 but not helix 9 were found to contain critical residues for substrate recognition. Mutation of arginine 306 to threonine in helix 8 resulted in strongly reduced transport activity. Concomitantly, saturable transport was transformed into a nonsaturable dependence of transport activity on lactate concentration, suggesting that binding of the substrate was strongly impaired. Furthermore, proton translocation in the mutant was partially uncoupled from monocarboxylate transport. Mutation of phenylalanine 360 to cysteine in helix 10 resulted in an altered substrate side chain recognition. In contrast to the wild-type transporter, monocarboxylates with more bulky and polar side chains were recognized by the mutated MCT1. Mutation of selected residues in helix 9 and helix 11 (C336A, H337Q, and E391Q) did not cause alterations of the transport properties of MCT1. It is suggested that substrate binding occurs in the carboxy-terminal half of MCT1 and that helices 8 and 10 are involved in the recognition of different parts of the substrate.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Rahman B,Schneider HP,Bröer A,Deitmer JW,Bröer S

doi

10.1021/bi990973f

subject

Has Abstract

pub_date

1999-08-31 00:00:00

pages

11577-84

issue

35

eissn

0006-2960

issn

1520-4995

pii

bi990973f

journal_volume

38

pub_type

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