POT transporters drive the concentrative uptake of their substrates by coupling to the transmembrane H+ electrochemical gradient. POTs recognize highly diverse di/tripeptides. Substrate extent expands with mammalian PepT1/PepT2, which also transport β-lactam antibiotics and peptide-based prodrugs. While substrate recognition changes, protonation sites seem conserved among members. In POTs, transport is achieved through the movement of the gating helices around the central binding site. The extracellular (EC) gate, formed by TM1,2 and TM7,8, serves to control access to the binding site from the EC side of the membrane. The intracellular (IC) gate, formed by TM4,5 and TM10,11, controls the release of peptide and protons on the inside of the cell. Two salt bridges coordinate these helices and control protein conformation. Whereas the IC gate contains a conserved Lys-Glu pair, the EC gate salt bridge is less conserved. In most of the bacterial POTs, the EC gate salt bridge is an Arg-Glu pair, while in mammalian PepT1, a conserved His on TM2 combined with an Arg-Asp salt bridge on TM1 and TM7 is seen. TM2 His is also found in “mammalian-like” bacterial members. In zebrafish PepT1b, the only vertebrate PepT1 known to work at alkaline pH, Lys replaces Arg on TM1. Likewise, PepT1 equally diverging from the “mammalian-like” transporters were retrieved (GenBank) from teleost fish (Cypriniformes, Cyprinodontiformes, Gymnotiformes, Gadiformes), birds (Apodiformes, Trochiliformes, Passeriformes, Piciformes), and even mammals (Chiroptera, Macroscelidea, Insectivora, Primates). Our findings extend the number of PepT1 prone to structure-function analyses and open to understand how their molecular diversity meets the physiology of the species and/or the environment where the species lives.

Diversity in proton movement and coupling to substrate in vertebrate PepT1 proteins: filling the gaps through the 'phylogenetic' approach

Bossi, E;Vacca, F;Cinquetti, R;
2019-01-01

Abstract

POT transporters drive the concentrative uptake of their substrates by coupling to the transmembrane H+ electrochemical gradient. POTs recognize highly diverse di/tripeptides. Substrate extent expands with mammalian PepT1/PepT2, which also transport β-lactam antibiotics and peptide-based prodrugs. While substrate recognition changes, protonation sites seem conserved among members. In POTs, transport is achieved through the movement of the gating helices around the central binding site. The extracellular (EC) gate, formed by TM1,2 and TM7,8, serves to control access to the binding site from the EC side of the membrane. The intracellular (IC) gate, formed by TM4,5 and TM10,11, controls the release of peptide and protons on the inside of the cell. Two salt bridges coordinate these helices and control protein conformation. Whereas the IC gate contains a conserved Lys-Glu pair, the EC gate salt bridge is less conserved. In most of the bacterial POTs, the EC gate salt bridge is an Arg-Glu pair, while in mammalian PepT1, a conserved His on TM2 combined with an Arg-Asp salt bridge on TM1 and TM7 is seen. TM2 His is also found in “mammalian-like” bacterial members. In zebrafish PepT1b, the only vertebrate PepT1 known to work at alkaline pH, Lys replaces Arg on TM1. Likewise, PepT1 equally diverging from the “mammalian-like” transporters were retrieved (GenBank) from teleost fish (Cypriniformes, Cyprinodontiformes, Gymnotiformes, Gadiformes), birds (Apodiformes, Trochiliformes, Passeriformes, Piciformes), and even mammals (Chiroptera, Macroscelidea, Insectivora, Primates). Our findings extend the number of PepT1 prone to structure-function analyses and open to understand how their molecular diversity meets the physiology of the species and/or the environment where the species lives.
Verri, T; Bossi, E; Barca, A; Del Vecchio, G; Mazzei, A; Piccinno, P; Vacca, F; Cinquetti, R; Murashita, K; Gomes, As; Ronnestad, I
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2086914
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