scholarly journals A non‐helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Dorota Focht ◽  
Caroline Neumann ◽  
Joseph Lyons ◽  
Ander Eguskiza Bilbao ◽  
Rickard Blunck ◽  
...  
Keyword(s):  
Amino Acid ◽  
Substrate Recognition ◽  
Transmembrane Helix ◽  
Amino Acid Transporter ◽  
Hydrophobic Amino Acid ◽  
Acid Transporter ◽  
Helical Region

scholarly journals Structural Insights Into Thyroid Hormone Transport Mechanisms of the L-Type Amino Acid Transporter 2

2015 ◽  
Vol 29 (6) ◽  
pp. 933-942 ◽  
Author(s):  
Katrin M. Hinz ◽  
Katja Meyer ◽  
Anita Kinne ◽  
Ralf Schülein ◽  
Josef Köhrle ◽  
...  
Keyword(s):  
Amino Acid ◽  
Molecular Mechanisms ◽  
Competitive Inhibition ◽  
Expression System ◽  
Transmembrane Helix ◽  
Amino Acid Transporter ◽  
Recognition Site ◽  
Side Chain ◽  
Xenopus Laevis Oocytes ◽  
Acid Transporter

Abstract Thyroid hormones (THs) are transported across cell membranes by different transmembrane transporter proteins. In previous studies, we showed marked 3,3′-diiodothyronine (3,3′-T2) but moderate T3 uptake by the L-type amino acid transporter 2 (Lat2). We have now studied the structure-function relationships of this transporter and TH-like molecules. Our Lat2 homology model is based on 2 crystal structures of the homologous 12-transmembrane helix transporters arginine/agmatine antiporter and amino acid/polyamine/organocation transporter. Model-driven mutagenesis of residues lining an extracellular recognition site and a TH-traversing channel identified 9 sensitive residues. Using Xenopus laevis oocytes as expression system, we found that side chain shortening (N51S, N133S, N248S, and Y130A) expanded the channel and increased 3,3′-T2 transport. Side chain enlargements (T140F, Y130R, and I137M) decreased 3,3′-T2 uptake, indicating channel obstructions. The opposite results with mutations maintaining (F242W) or impairing (F242V) uptake suggest that F242 may have a gating function. Competitive inhibition studies of 14 TH-like compounds revealed that recognition by Lat2 requires amino and carboxylic acid groups. The size of the adjacent hydrophobic group is restricted. Bulky substituents in positions 3 and 5 of the tyrosine ring are allowed. The phenolic ring may be enlarged, provided that the whole molecule is flexible enough to fit into the distinctly shaped TH-traversing channel of Lat2. Taken together, the next Lat2 features were identified 1) TH recognition site; 2) TH-traversing channel in the center of Lat2; and 3) switch site that potentially facilitates intracellular substrate release. Together with identified substrate features, these data help to elucidate the molecular mechanisms and role of Lat2 in T2 transport.

Substrate recognition by the mammalian proton-dependent amino acid transporter PAT1

2003 ◽  
Vol 20 (3) ◽  
pp. 261-269 ◽  
Author(s):  
Michael Boll ◽  
Martin Foltz ◽  
Catriona M. H. Anderson ◽  
Carmen Oechsler ◽  
Gabor Kottra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Substrate Recognition ◽  
Amino Acid Transporter ◽  
Acid Transporter

scholarly journals Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc

2019 ◽  
Author(s):  
Yongchan Lee ◽  
Pattama Wiriyasermkul ◽  
Chunhuan Jin ◽  
Lili Quan ◽  
Ryuichi Ohgaki ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Transmembrane Helix ◽  
Amino Acid Transporter ◽  
Molecular Assembly ◽  
Surface Glycoprotein ◽  
Binding Modes ◽  
Cell Surface Glycoprotein ◽  
Solute Carrier ◽  
Acid Transporter

SummaryThe L-type amino acid transporter 1 (LAT1) transports large neutral amino acids and drugs across the plasma membrane and is crucial for nutrient uptake, brain drug delivery and tumor growth. LAT1 is a unique solute carrier that forms a disulfide-linked heterodimer with the cell-surface glycoprotein CD98 heavy chain (CD98hc), but the mechanisms of its molecular assembly and amino acid transport are poorly understood. Here we report the cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.4 Å resolution, revealing the hitherto unprecedented architecture of a solute carrier-glycoprotein heterocomplex. LAT1 features a canonical LeuT-fold while exhibiting an unusual loop structure on transmembrane helix 6, creating an extended cavity to accommodate bulky hydrophobic amino acids and drugs. CD98hc engages with LAT1 through multiple interactions, not only in the extracellular and transmembrane domains but also in the interdomain linker. The heterodimer interface features multiple sterol molecules, corroborating previous biochemical data on the role of cholesterols in heterodimer stabilization. We also visualized the binding modes of two anti-CD98 antibodies and show that they recognize distinct, multiple epitopes on CD98hc but not its glycans, explaining their robust reactivities despite the glycan heterogeneity. Furthermore, we mapped disease-causing mutations onto the structure and homology models, which rationalized some of the phenotypes of SLC3- and SLC7-related congenital disorders. Together, these results shed light on the principles of the structural assembly between a glycoprotein and a solute carrier, and provide a template for improving preclinical drugs and therapeutic antibodies targeting LAT1 and CD98.

Transport of Amino Acid-Related Compounds Mediated by L-Type Amino Acid Transporter 1 (LAT1): Insights Into the Mechanisms of Substrate Recognition

2002 ◽  
Vol 61 (4) ◽  
pp. 729-737 ◽  
Author(s):  
Hiroshi Uchino ◽  
Yoshikatsu Kanai ◽  
Do Kyung Kim ◽  
Michael F. Wempe ◽  
Arthit Chairoungdua ◽  
...  
Keyword(s):  
Amino Acid ◽  
Substrate Recognition ◽  
Amino Acid Transporter ◽  
Acid Transporter ◽  
Related Compounds

Increased expression of an amino acid transporter LAT1 in healing of acetic acid-induced chronic gastric ulcer in rats

2001 ◽  
Vol 120 (5) ◽  
pp. A153-A153
Author(s):  
S MIYAMOTO ◽  
K KATO ◽  
Y ISHII ◽  
S ASAI ◽  
T NAGAISHI ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Gastric Ulcer ◽  
Amino Acid ◽  
Amino Acid Transporter ◽  
Chronic Gastric Ulcer ◽  
Acid Transporter
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