Experimentally optimized threading structures of the proton-coupled folate transporter.

Abstract:

:The proton-coupled folate transporter (PCFT, SLC46A1) transports folic acid across the plasma membrane, together with an excess of protons such that the net charge translocation is positive. We developed 3D structural models of PCFT threaded onto the X-ray structures of major facilitator superfamily (MFS) members that were identified as close structural homologues. The model of PCFT threaded onto the glycerol-3-phosphate transporter (GlpT) structure is consistent with detailed accessibility studies in the absence of extracellular substrate and at pH 7.4 presented here, and additionally with a multitude of other mutagenesis and functional studies. Characteristic MFS structural features are preserved in this PCFT model, such as 12 transmembrane helices divided into two pseudosymmetric bundles, and a high density of positive charges on the periphery of the cytoplasmic site that allow interactions with negatively charged lipid head-groups. Under the experimental conditions, PCFT predominantly samples the resting state, which in this case is inward-open. Several positions lining the substrate cavity have been identified. Motif A, a helix-turn-helix motif that is a hallmark of MFS transporters between transmembrane segments II and III is oriented appropriately to interact with residues from transmembrane segments IV as well as XI upon conformational transition to the outward-open state. A charge-relay system between three charged residues as well as apposing glycines in two α-helices, both contributed to by motif A, become engaged when PCFT is modeled on the outward-open state of a putative proton-driven transporter (YajR).

journal_name

FEBS Open Bio

journal_title

FEBS open bio

authors

Date SS,Chen CY,Chen Y,Jansen M

doi

10.1002/2211-5463.12041

subject

Has Abstract

pub_date

2016-02-22 00:00:00

pages

216-30

issue

3

issn

2211-5463

pii

FEB412041

journal_volume

6

pub_type

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