Crystal Structures of the Extracellular Domain from PepT1 and PepT2 Provide Novel Insights into Mammalian Peptide Transport

Structure
John H BealeSimon Newstead

Abstract

Mammals obtain nitrogen via the uptake of di- and tri-peptides in the gastrointestinal tract through the action of PepT1 and PepT2, which are members of the POT family of proton-coupled oligopeptide transporters. PepT1 and PepT2 also play an important role in drug transport in the human body. Recent crystal structures of bacterial homologs revealed a conserved peptide-binding site and mechanism of transport. However, a key structural difference exists between bacterial and mammalian homologs with only the latter containing a large extracellular domain, the function of which is currently unknown. Here, we present the crystal structure of the extracellular domain from both PepT1 and PepT2 that reveal two immunoglobulin-like folds connected in tandem, providing structural insight into mammalian peptide transport. Functional and biophysical studies demonstrate that these domains interact with the intestinal protease trypsin, suggesting a role in clustering proteolytic activity to the site of peptide transport in eukaryotic cells.

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Citations

Oct 9, 2015·Structure·Joseph A Lyons, Poul Nissen
Mar 31, 2016·Cell Chemical Biology·Firdaus SamsudinPhilip W Fowler
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Nov 21, 2015·American Journal of Physiology. Gastrointestinal and Liver Physiology·Tamara StelzlHannelore Daniel
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Nov 8, 2017·Molecular Pharmaceutics·Claire ColasAvner Schlessinger
Oct 13, 2021·Protein Expression and Purification·Maria RafiqOsman Mirza

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Methods Mentioned

BETA
size-exclusion chromatography
X-ray
surface plasmon resonance
microscale thermophoresis
chip
PCR
in vitro transcription

Software Mentioned

Jalview
PRIMUS
NanoTemper
DAMAVER
BUSTER
PHENIX
SHELXC
SHARP
Sculptor
Phaser

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