Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Proc Natl Acad Sci U S A ; 118(49)2021 12 07.
Article in English | MEDLINE | ID: mdl-34848541

ABSTRACT

Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity determines the physiological function of each HAT and their role in human diseases. However, HAT transport preference for some amino acids over others is not yet fully understood. Using cryo-electron microscopy of apo human LAT2/CD98hc and a multidisciplinary approach, we elucidate key molecular determinants governing neutral amino acid specificity in HATs. A few residues in the substrate-binding pocket determine substrate preference. Here, we describe mutations that interconvert the substrate profiles of LAT2/CD98hc, LAT1/CD98hc, and Asc1/CD98hc. In addition, a region far from the substrate-binding pocket critically influences the conformation of the substrate-binding site and substrate preference. This region accumulates mutations that alter substrate specificity and cause hearing loss and cataracts. Here, we uncover molecular mechanisms governing substrate specificity within the HAT family of neutral amino acid transporters and provide the structural bases for mutations in LAT2/CD98hc that alter substrate specificity and that are associated with several pathologies.


Subject(s)
Amino Acid Transport Systems, Neutral/physiology , Substrate Specificity/physiology , Adaptor Proteins, Signal Transducing/metabolism , Amino Acid Transport Systems/metabolism , Amino Acid Transport Systems/physiology , Amino Acid Transport Systems, Neutral/metabolism , Amino Acids/metabolism , Amino Acids, Neutral/metabolism , Biological Transport/physiology , Cryoelectron Microscopy/methods , Fusion Regulatory Protein 1, Heavy Chain/metabolism , HeLa Cells , Humans , Large Neutral Amino Acid-Transporter 1/metabolism , Protein Domains , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...