Structural biology of solute carrier (SLC) membrane transport proteins

Abstract

The human solute carriers (SLCs) comprise over 400 different transporters, organized into 65 families (http://slc.bioparadigms.org/) based on their sequence homology and transport function. SLCs are responsible for transporting extraordinarily diverse solutes across biological membranes, including inorganic ions, amino acids, lipids, sugars, neurotransmitters and drugs. Most of these membrane proteins function as coupled symporters (co-transporters) utilizing downhill ion (H þ or Na þ) gradients as the driving force for the transport of substrate against its concentration gradient into cells. Other members work as antiporters (exchangers) that typically contain a single substrate-binding site with an alternating access mode of transport, while a few members exhibit channel-like properties. Dysfunction of SLCs is correlated with numerous human diseases and therefore they are potential therapeutic drug targets. In this review, we identified all of the SLC crystal structures that have been determined, most of which are from prokaryotic species. We further sorted all the SLC structures into four main groups with different protein folds and further discuss the well-characterized MFS (major facilitator superfamily) and LeuT (leucine transporter) folds. This review provides a systematic analysis of the structure, molecular basis of substrate recognition and mechanism of action in different SLC family members.

Structure of the human cation–chloride cotransporter NKCC1 determined by single-particle electron cryo-microscopy

“…CCCs belong to the large amino acid-polyamine-organocation (APC) superfamily of transporters. Structures of several APC transporters demonstrate that they all exhibit a rough twofold symmetry such that two inverted repeats of five transmembrane (TM) helices together form a central substrate binding cavity 21,22 . This pseudo-symmetric topology of two inverted repeats is the linchpin of the alternating-access mechanism whereby transporters isomerize among outward-open, occluded, and inward-open states to translocate substrates across membranes 23 .…”

Hydrogen-Deuterium Exchange Mass-Spectrometry of Secondary Active Transporters: From Structural Dynamics to Molecular Mechanisms

“…Secondary transporters comply with the alternating access paradigm, according to which the protein ligand-binding pocket becomes alternatively accessible at opposite sides of the membrane by adopting the inward-facing (IF) and outwardfacing (OF) states in succession (Jardetzky, 1966;Forrest et al, 2011). Recent breakthroughs in the structural biology of membrane proteins provided a wealth of structures of membrane-bound transporters in different conformational states (Drew and Boudker, 2016;Bai et al, 2017), providing insights into their transport and solute recognition mechanisms. However, they provide static snapshots of an inherently multistep process (Seeger, 2018).…”

Hydrogen-deuterium exchange mass spectrometry captures distinct dynamics upon substrate and inhibitor binding to a transporter

“…Biochemical studies and MD simulations have shown that protonation must occur before xylose binding but it is not clear whether E206, D27 or both are protonated [19,22]. Furthermore, the structures of the xylose-bound and glucose-bound protein are virtually identical, with only minor differences in the interaction network at the binding site [23]. This observation raises questions on how the transporter discriminates between substrate and inhibitor and how the potential differences are translated into conformational changes.…”