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Crystal structures of the extracellular domain from PepT1 and PepT2 provide novel insights into mammalian pPeptide transport

Beale, John H.; Parker, Joanne L.; Samsudin, Firdaus; Barrett, Anne L.; Senan, Anish; Bird, Louise E.; Scott, David; Owens, Raymond J.; Sansom, Mark S.P.; Tucker, Stephen J.; Meredith, David; Fowler, Philip W.; Newstead, Simon

Authors

John H. Beale

Joanne L. Parker

Firdaus Samsudin

Anne L. Barrett

Anish Senan

Louise E. Bird

DAVID SCOTT david.scott@nottingham.ac.uk
Associate Professor & Reader Inphysical Biochemistry

Raymond J. Owens

Mark S.P. Sansom

Stephen J. Tucker

David Meredith

Philip W. Fowler

Simon 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.

Journal Article Type Article
Publication Date Oct 6, 2015
Journal Structure (London, England : 1993)
Print ISSN 0969-2126
Electronic ISSN 1878-4186
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 23
Issue 10
APA6 Citation Beale, J. H., Parker, J. L., Samsudin, F., Barrett, A. L., Senan, A., Bird, L. E., …Newstead, S. (2015). Crystal structures of the extracellular domain from PepT1 and PepT2 provide novel insights into mammalian pPeptide transport. Structure, 23(10), https://doi.org/10.1016/j.str.2015.07.016
DOI https://doi.org/10.1016/j.str.2015.07.016
Publisher URL http://www.sciencedirect.com/science/article/pii/S0969212615003226
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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