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Title: Cryo-EM structure of the human neutral amino acid transporter ASCT2

Human ASCT2 belongs to the SLC1 family of secondary transporters and is specific for the transport of small neutral amino acids. ASCT2 is upregulated in cancer cells and serves as the receptor for many retroviruses; hence, it has importance as a potential drug target. Here we used single-particle cryo-EM to determine a structure of the functional and unmodified human ASCT2 at 3.85-Å resolution. ASCT2 forms a homotrimeric complex in which each subunit contains a transport and a scaffold domain. Prominent extracellular extensions on the scaffold domain form the predicted docking site for retroviruses. Relative to structures of other SLC1 members, ASCT2 is in the most extreme inward-oriented state, with the transport domain largely detached from the central scaffold domain on the cytoplasmic side. In conclusion, this domain detachment may be required for substrate binding and release on the intracellular side of the membrane.
Authors:
 [1] ; ORCiD logo [1] ;  [2] ; ORCiD logo [1] ;  [1] ; ORCiD logo [1]
  1. Univ. of Groningen, Groningen (The Netherlands)
  2. SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., Stanford, CA (United States)
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 25; Journal Issue: 6; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1475494

Garaeva, Alisa A., Oostergetel, Gert T., Gati, Cornelius, Guskov, Albert, Paulino, Cristina, and Slotboom, Dirk J.. Cryo-EM structure of the human neutral amino acid transporter ASCT2. United States: N. p., Web. doi:10.1038/s41594-018-0076-y.
Garaeva, Alisa A., Oostergetel, Gert T., Gati, Cornelius, Guskov, Albert, Paulino, Cristina, & Slotboom, Dirk J.. Cryo-EM structure of the human neutral amino acid transporter ASCT2. United States. doi:10.1038/s41594-018-0076-y.
Garaeva, Alisa A., Oostergetel, Gert T., Gati, Cornelius, Guskov, Albert, Paulino, Cristina, and Slotboom, Dirk J.. 2018. "Cryo-EM structure of the human neutral amino acid transporter ASCT2". United States. doi:10.1038/s41594-018-0076-y.
@article{osti_1475494,
title = {Cryo-EM structure of the human neutral amino acid transporter ASCT2},
author = {Garaeva, Alisa A. and Oostergetel, Gert T. and Gati, Cornelius and Guskov, Albert and Paulino, Cristina and Slotboom, Dirk J.},
abstractNote = {Human ASCT2 belongs to the SLC1 family of secondary transporters and is specific for the transport of small neutral amino acids. ASCT2 is upregulated in cancer cells and serves as the receptor for many retroviruses; hence, it has importance as a potential drug target. Here we used single-particle cryo-EM to determine a structure of the functional and unmodified human ASCT2 at 3.85-Å resolution. ASCT2 forms a homotrimeric complex in which each subunit contains a transport and a scaffold domain. Prominent extracellular extensions on the scaffold domain form the predicted docking site for retroviruses. Relative to structures of other SLC1 members, ASCT2 is in the most extreme inward-oriented state, with the transport domain largely detached from the central scaffold domain on the cytoplasmic side. In conclusion, this domain detachment may be required for substrate binding and release on the intracellular side of the membrane.},
doi = {10.1038/s41594-018-0076-y},
journal = {Nature Structural & Molecular Biology},
number = 6,
volume = 25,
place = {United States},
year = {2018},
month = {6}
}

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