A one-gate elevator mechanism for the human neutral amino acid transporter ASCT2

Nature Communications
Alisa A GaraevaCristina Paulino

Abstract

The human Alanine Serine Cysteine Transporter 2 (ASCT2) is a neutral amino acid exchanger that belongs to the solute carrier family 1 (SLC1A). SLC1A structures have revealed an elevator-type mechanism, in which the substrate is translocated across the cell membrane by a large displacement of the transport domain, whereas a small movement of hairpin 2 (HP2) gates the extracellular access to the substrate-binding site. However, it has remained unclear how substrate binding and release is gated on the cytoplasmic side. Here, we present an inward-open structure of the human ASCT2, revealing a hitherto elusive SLC1A conformation. Strikingly, the same structural element (HP2) serves as a gate in the inward-facing as in the outward-facing state. The structures reveal that SLC1A transporters work as one-gate elevators. Unassigned densities near the gate and surrounding the scaffold domain, may represent potential allosteric binding sites, which could guide the design of lipidic-inhibitors for anticancer therapy.

References

Jun 5, 1999·Microbiology and Molecular Biology Reviews : MMBR·D J SlotboomJ S Lolkema
Sep 9, 2000·The Journal of Biological Chemistry·A BendahanB I Kanner
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Nov 21, 2009·Proceedings of the National Academy of Sciences of the United States of America·Thomas J CrismanLucy R Forrest
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
May 14, 2010·Nature·Yongfang ZhaoJonathan A Javitch
Jun 24, 2010·Trends in Biochemical Sciences·David R Wise, Craig B Thompson
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Jul 31, 2012·Nature Methods·Sjors H W Scheres, Shaoxia Chen
Mar 20, 2013·Molecular Aspects of Medicine·Yoshikatsu KanaiMatthias A Hediger
Apr 13, 2013·The Journal of General Virology·Sayumi ShimodeTakayuki Miyazawa
Apr 16, 2013·Nature Reviews. Cancer·Darren J Burgess
Sep 10, 2013·Nature Structural & Molecular Biology·Sonja JensenDirk Jan Slotboom
Sep 17, 2013·ELife·Andrew MorinPiotr Sliz
Aug 19, 2015·Journal of Structural Biology·Alexis Rohou, Nikolaus Grigorieff
Nov 26, 2015·Oncogene·L JinS Kang
Mar 28, 2017·Journal of Structural Biology·Nikhil BiyaniHenning Stahlberg
Apr 21, 2017·Nature·Juan C Canul-TecNicolas Reyes
Jul 16, 2017·Protein Science : a Publication of the Protein Society·Thomas D GoddardThomas E Ferrin
Jun 7, 2018·Nature Structural & Molecular Biology·Alisa A GaraevaDirk J Slotboom
Jul 22, 2018·European Journal of Pharmacology·Yang LiuLi Sun

❮ Previous
Next ❯

Citations

Oct 31, 2019·International Journal of Molecular Sciences·Verena BurtscherWalter Sandtner
Feb 23, 2020·Nature Communications·Valentina ArkhipovaDirk J Slotboom
Apr 15, 2020·Current Protocols in Protein Science·Lucile GuyotRenaud Wagner
Apr 4, 2020·The Biochemical Journal·Elias NdaruChristof Grewer
May 6, 2020·Biochemical Society Transactions·Alisa A Garaeva, Dirk J Slotboom
Nov 12, 2019·Frontiers in Molecular Biosciences·Mariafrancesca ScaliseCesare Indiveri
Aug 1, 2020·Frontiers in Cell and Developmental Biology·Mariafrancesca ScaliseCesare Indiveri
Aug 25, 2020·The Journal of General Physiology·Jiali WangChristof Grewer
Oct 8, 2020·Nature Communications·Tina R MatinSimon Scheuring
Aug 21, 2020·The Journal of Biological Chemistry·Bettina KolenChristoph Fahlke
Sep 15, 2019·Trends in Pharmacological Sciences·Rachel-Ann A Garibsingh, Avner Schlessinger
Nov 28, 2019·Journal of Medicinal Chemistry·Wesley WangChristopher G Parker
Feb 16, 2021·Neurochemical Research·Claudia AllevaChristoph Fahlke
Nov 14, 2020·The EMBO Journal·Gerard H M HuysmansOlga Boudker
May 1, 2021·Frontiers in Cellular Neuroscience·Renae M RyanAnnalisa Scimemi
May 6, 2021·Acta Crystallographica. Section D, Structural Biology·Jan RheinbergerCristina Paulino
May 2, 2021·FEBS Open Bio·Cristina CecchettiBernadette Byrne
Jun 19, 2021·Communications Biology·Gianluca TrincoDirk J Slotboom
Jul 17, 2021·SLAS Discovery·Mariafrancesca ScaliseCesare Indiveri
Sep 6, 2019·Journal of Agricultural and Food Chemistry·Xiubing WuJing Zhang
Sep 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Rachel-Ann A GaribsinghAvner Schlessinger
Nov 9, 2021·The EMBO Journal·Juan C Canul-TecNicolas Reyes
Dec 8, 2021·Proceedings of the National Academy of Sciences of the United States of America·Didar CiftciOlga Boudker

❮ Previous
Next ❯

Methods Mentioned

BETA
size-exclusion chromatography

Software Mentioned

PyMOL
Chimera
FOCUS
MotionCor2
MolProbity
ctffind4
ChimeraX
Relion3
RELION
PyMOL Molecular Graphics System

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.