Abstract
The POT family of proton coupled oligopeptide transporters belong to the Major Facilitator Superfamily of secondary active transporters and are found widely distributed in bacterial, plant, fungal and animal genomes. POT transporters use the inwardly directed proton electrochemical gradient to drive the concentrative uptake of di- and tri-peptides across the cell membrane for metabolic assimilation. Mammalian members of the family, PepT1 and PepT2, are responsible for the uptake and retention of dietary protein in the human body, and due to their promiscuity in ligand recognition, play important roles in the pharmacokinetics of drug transport. Recent crystal structures of bacterial and plant members have revealed the overall architecture for this protein family and provided a framework for understanding proton coupled transport within the POT family. An interesting outcome from these studies has been the discovery of symmetrically equivalent structural and functional sites. This review will highlight both the symmetry and asymmetry in structure and function within the POT family and discuss the implications of these considerations in understanding transport and regulation.
Highlights
The uptake and retention of dietary peptides in mammals is carried out by the plasma membrane transporters, PepT1 (SLC15A1) and PepT2 (SLC15A2) [1,2], which are expressed in the cells of the small intestine and kidney respectively
major facilitator superfamily (MFS) transporters operate via POT family members structural features support this model, including an alternatinghave accessrevealed mechanism,conserved wherein a central ligand binding site is that alternately exposed to either side of the membrane in response to ligand binding
One of the major outcomes from the structural studies on secondary active transporters in recent years has been the importance of symmetry [20,42]
Summary
The uptake and retention of dietary peptides in mammals is carried out by the plasma membrane transporters, PepT1 (SLC15A1) and PepT2 (SLC15A2) [1,2], which are expressed in the cells of the small intestine and kidney respectively. Rather uniquely MFS amongtransporters secondary active operate transporters these two domains functionally connect only through side chain interactions, without any crossing over of access mechanism, wherein a central ligand binding site is alternately exposed to either side of the the back-bone chain. MFS transporters operate via POT family members structural features support this model, including an alternatinghave accessrevealed mechanism,conserved wherein a central ligand binding site is that alternately exposed to either side of the membrane in response to ligand binding [16]. MFS transporters are composed of two six helical bundles that through the opening and closing of two gates that sit on either side of a central binding site and which sit in the membrane in a out “V”. C-terminal bundle, which are Proton conserved binding sitesthe act to drive the transport the inverted many POT family members two salt bridge interactions cycle intopology the forward repeat direction,units. Proton binding/release from conserved proton binding sites act to drive the transport cycle in the forward direction, thereby concentrating peptides inside the cell
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