Extracellular Domain of PepT1 Interacts With TM1 to Facilitate Substrate Transport

Authors

Jiemin Shen
Miaohui Hu
Xiao Fan
Zhenning Ren
Corinne Portioli
Xiuwen Yan
Mingqiang Rong
Ming Zhou

Publication Date

7-7-2022

Journal

Structure

DOI

10.1016/j.str.2022.04.011

PMID

35580608

PMCID

PMC10404463

PubMedCentral® Posted Date

8-6-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Animals, Biological Transport, Horses, Mammals, Molecular Conformation, Peptide Transporter 1, Peptides, Symporters

Abstract

Mammalian peptide transporters, PepT1 and PepT2, mediate uptake of small peptides and are essential for their absorption. PepT also mediates absorption of many drugs and prodrugs to enhance their bioavailability. PepT has twelve transmembrane (TM) helices that fold into an N-terminal domain (NTD, TM1–6) and a C-terminal domain (CTD, TM7–12), and has a large extracellular domain (ECD) between TM9–10. It is well-recognized that peptide transport requires movements of the NTD and CTD, but the role of the ECD in PepT1 remains unclear. Here we report the structure of horse PepT1 encircled in lipid nanodiscs and captured in the inward-open apo conformation. The structure shows that the ECD bridges the NTD and CTD by interacting with TM1. Deletion of ECD or mutations to the ECD-TM1 interface impairs the transport activity. These results demonstrate an important role of ECD in PepT1 and enhance our understanding of the transport mechanism in PepT1.

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