Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology

Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers

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Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology Stephen J. Fairweather, Nishank Shah, and Stefan Brӧer

Abstract

Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology – all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively

detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+ATrBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture. Keywords

Heteromeric solute carriers · Membrane transporters · Solute carriers · SLC · Membrane physiology · Ancillary proteins · Auxillary proteins · Molecular chaperones · LAT14F2hc structure · CD98 · SLC6 · SLC7 · SLC3 · AE1 · Band 3 · CD147 · Glycophorin A · Syntaxin 1A · Ost α-Ost β · B0AT1 · ACE2 · Collectrin · Blood group antigens · SLC16 · SLC4 · SLC51 · Basigin · Embigin

Abbreviations S. J. Fairweather (*) Research School of Biology, Australian National University, Canberra, ACT, Australia Resarch School of Chemistry, Australian National University, Canberra, ACT, Australia e-mail: [email protected] N. Shah · S. Brӧer (*) Research School of Biology, Australian National University, Canberra, ACT, Australia e-mail: [email protected]

AA APC APN ACE2 AE1 mAbs

Amino Acids Amino Acid-Polyamine-Organocation Transporter Family Aminopeptidase N Angiotensin Converting Enzyme 2 Anion Exchanger 1 monoclonal Antibodies

S. J. Fairweather et al.

ADHD ASD BCH B0AT1/3 CA CD CHS DHEAS DAT EC ER ERAD FGF FXR GAT GSH GLYT1/2 GPA/B/C HS HMM ISF KO L-DOPA LPI MeAIB MCT NFPS

NET NSS OMIM pCMBS PPI RBC dRTA RPE RdCVF SERT SAO SAR

Attention Deficit Hyperactivity Disorder Autism Spectrum Disorder 2-aminobicyclo-(2,2,1)-heptane-2carboxylic acid Broad Neutral Amino acid Transporter 1/3 Carbonic Anhydrase Cluster of Differentiation Cholesterol hemisuccinate Dehydroepiandrosterone Dopamine Transporter Extracellular Endoplasmic Reticulum Endoplasmic Reticulum Associated Degradation Fibroblast Growth Factor Farnesoid X receptor GABA Transporter Glutathione Glycine Transporter 1/2 Glycopho