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Structure. 2015 Oct 6;23(10):1889-1899. doi: 10.1016/j.str.2015.07.016. Epub 2015 Aug 27.

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

Author information

1
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
2
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK.
3
Department of Biological Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
4
Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK; OPPF-UK, Research Complex at Harwell, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK.
5
Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0FA, UK; ISIS Spallation Neutron and Muon Source, Rutherford Appleton Laboratory, Oxfordshire OX11 0FA, UK; School of Biosciences, School of Biosciences, Sutton Bonington Campus, Leicestershire LE12 5RD, UK.
6
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Membrane Transport, University of Oxford OX1 3PU, UK.
7
Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK; OXION Initiative in Ion Channels and Membrane Transport, University of Oxford OX1 3PU, UK.
8
Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
9
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; OXION Initiative in Ion Channels and Membrane Transport, University of Oxford OX1 3PU, UK. Electronic address: simon.newstead@bioch.ox.ac.uk.

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.

PMID:
26320580
PMCID:
PMC4597091
DOI:
10.1016/j.str.2015.07.016
[Indexed for MEDLINE]
Free PMC Article

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