TY - JOUR
T1 - A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1
AU - Stehantsev, Pavlo
AU - Stetsenko, Artem
AU - Nemchinova, Mariia
AU - Aduri, Nanda Gowtham
AU - Marrink, Siewert
AU - Gati, Cornelius
AU - Guskov, Albert
PY - 2021/10
Y1 - 2021/10
N2 - The ASCT1 transporter of the SLC1 family is largely involved in equilibration of neutral amino acids’ pools across the plasma membrane and plays a prominent role in the transport of both L- and D-isomers of serine, essential for the normal functioning of the central nervous system in mammals. A number of mutations in ASCT1 (E256K, G381R, R457W) have been linked to severe neurodevelopmental disorders, however in the absence of ASCT1 structure it is hard to understand their impact on substrate transport. To ameliorate that we have determined a cryo-EM structure of human ASCT1 at 4.2 Å resolution and performed functional transport assays and molecular dynamics simulations, which revealed that given mutations lead to the diminished transport capability of ASCT1 caused by instability of transporter and impeded transport cycle.
AB - The ASCT1 transporter of the SLC1 family is largely involved in equilibration of neutral amino acids’ pools across the plasma membrane and plays a prominent role in the transport of both L- and D-isomers of serine, essential for the normal functioning of the central nervous system in mammals. A number of mutations in ASCT1 (E256K, G381R, R457W) have been linked to severe neurodevelopmental disorders, however in the absence of ASCT1 structure it is hard to understand their impact on substrate transport. To ameliorate that we have determined a cryo-EM structure of human ASCT1 at 4.2 Å resolution and performed functional transport assays and molecular dynamics simulations, which revealed that given mutations lead to the diminished transport capability of ASCT1 caused by instability of transporter and impeded transport cycle.
U2 - 10.1016/j.csbj.2021.09.015
DO - 10.1016/j.csbj.2021.09.015
M3 - Article
SN - 2001-0370
VL - 19
SP - 5246
EP - 5254
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
ER -