Structural basis of proton-coupled potassium transport in the KUP family.
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ABSTRACT:
SUBMITTER: Tascon I
PROVIDER: S-EPMC6994465 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The POT family of membrane transporters use the inwardly directed proton electrochemical gradient to drive the uptake of essential nutrients into the cell. Originally discovered in bacteria, members of the family have been found in all kingdoms of life except the archaea. A remarkable feature of the family is their diverse substrate promiscuity. Whereas in mammals and bacteria they are predominantly di- and tri-peptide transporters, in plants the family has diverged to recognize nitrate, plant defence compounds and hormones. This promiscuity has led to the development of peptide-based pro-drugs that use PepT1 and PepT2, the mammalian homologues, to improve oral drug delivery. Recent crystal structures from bacterial and plant members of the family have revealed conserved features of the ligand-binding site and provided insights into post-translational regulation. Here I review the current understanding of transport, ligand promiscuity and regulation within the POT family.
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Project description:BackgroundCellular uptake of small peptides is an important physiological process mediated by the PTR family of proton-coupled peptide transporters. In bacteria peptides can be used as a source of amino acids and nitrogen. Similarly in humans peptide transport is the principle route for the uptake and retention of dietary protein in the form of short di- and tri-peptides for cellular metabolism.Scope of the reviewRecent crystal structures of bacterial PTR family transporters, combined with biochemical studies of transport have revealed key molecular details underpinning ligand promiscuity and the mechanism of proton-coupled transport within the family.Major conclusionsPairs of salt bridge interactions between transmembrane helices work in tandem to orchestrate alternating access transport within the PTR family. Key roles for residues conserved between bacterial and eukaryotic homologues suggest a conserved mechanism of peptide recognition and transport that in some cases has been subtly modified in individual species.General significancePhysiological studies on PepT1 and PepT2, the mammalian members of this family, have identified these transporters as being responsible for the uptake of many pharmaceutically important drug molecules, including antibiotics and antiviral medications and demonstrated their promiscuity can be used for improving the oral bioavailability of poorly absorbed compounds. The insights gained from recent structural studies combined with previous physiological and biochemical analyses are rapidly advancing our understanding of this medically important transporter superfamily. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
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