TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Anderson, Catriona M. H.
A1  - Edwards, Noel
A1  - Watson, Andrew K.
A1  - Althaus, Mike
A1  - Thwaites, David T.
T1  - Reshaping the Binding Pocket of the Neurotransmitter:Solute Symporter (NSS) Family Transporter SLC6A14 (ATB0,+) Selectively Reduces Access for Cationic Amino Acids and Derivatives
JF  - Biomolecules
N2  - SLC6A14 (ATB0,+) is unique among SLC proteins in its ability to transport 18 of the 20 proteinogenic (dipolar and cationic) amino acids and naturally occurring and synthetic analogues (including anti-viral prodrugs and nitric oxide synthase (NOS) inhibitors). SLC6A14 mediates amino acid uptake in multiple cell types where increased expression is associated with pathophysiological conditions including some cancers. Here, we investigated how a key position within the core LeuT-fold structure of SLC6A14 influences substrate specificity. Homology modelling and sequence analysis identified the transmembrane domain 3 residue V128 as equivalent to a position known to influence substrate specificity in distantly related SLC36 and SLC38 amino acid transporters. SLC6A14, with and without V128 mutations, was heterologously expressed and function determined by radiotracer solute uptake and electrophysiological measurement of transporter-associated current. Substituting the amino acid residue occupying the SLC6A14 128 position modified the binding pocket environment and selectively disrupted transport of cationic (but not dipolar) amino acids and related NOS inhibitors. By understanding the molecular basis of amino acid transporter substrate specificity we can improve knowledge of how this multi-functional transporter can be targeted and how the LeuT-fold facilitates such diversity in function among the SLC6 family and other SLC amino acid transporters.
KW  - APC superfamily
KW  - Membrane Transport
KW  - NSS family
KW  - SLC6A14
KW  - ATB0,+
KW  - SLC6
KW  - SLC
KW  - LeuT
KW  - amino acid transporter
KW  - solute carrier
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-64519
SN  - 2218-273X
SS  - 2218-273X
U6  - https://doi.org/10.3390/biom12101404
DO  - https://doi.org/10.3390/biom12101404
PM  - 36291613
VL  - 12
IS  - 10
SP  - 19
S1  - 19
PB  - MDPI
ER  -