Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2

Hu, Wenxin; Song, Alex; Zheng, Hongjin

doi:10.1038/s41467-024-48028-3

Title: Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2

Journal Article · 29 April 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-48028-3 · OSTI ID:2471638

^[1]; Song, Alex ^[1];

^[1]

University of Colorado Anschutz Medical Campus, Aurora, CO (United States)

SLC26A2 is a vital solute carrier responsible for transporting essential nutritional ions, including sulfate, within the human body. Pathogenic mutations within SLC26A2 give rise to a spectrum of human diseases, ranging from lethal to mild symptoms. The molecular details regarding the versatile substrate-transporter interactions and the impact of pathogenic mutations on SLC26A2 transporter function remain unclear. Here, using cryo-electron microscopy, we determine three high-resolution structures of SLC26A2 in complexes with different substrates. These structures unveil valuable insights, including the distinct features of the homodimer assembly, the dynamic nature of substrate binding, and the potential ramifications of pathogenic mutations. This structural-functional information regarding SLC26A2 will advance our understanding of cellular sulfate transport mechanisms and provide foundations for future therapeutic development against various human diseases.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH)

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2471638

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (56)

GROMACS: Fast, flexible, and free Van Der Spoel, David; Lindahl, Erik; Hess, Berk Journal of Computational Chemistry, Vol. 26, Issue 16 https://doi.org/10.1002/jcc.20291	journal	January 2005
CHARMM-GUI: A web-based graphical user interface for CHARMM Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G. Journal of Computational Chemistry, Vol. 29, Issue 11 https://doi.org/10.1002/jcc.20945	journal	March 2008
CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields Vanommeslaeghe, K.; Hatcher, E.; Acharya, C. Journal of Computational Chemistry https://doi.org/10.1002/jcc.21367	journal	January 2009
Extension of the CHARMM general force field to sulfonyl-containing compounds and its utility in biomolecular simulations Yu, Wenbo; He, Xibing; Vanommeslaeghe, Kenno Journal of Computational Chemistry, Vol. 33, Issue 31 https://doi.org/10.1002/jcc.23067	journal	July 2012
UCSF ChimeraX : Structure visualization for researchers, educators, and developers Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Protein Science, Vol. 30, Issue 1 https://doi.org/10.1002/pro.3943	journal	October 2020
Spatial arrangement of proteins in planar and curved membranes by PPM 3.0 Lomize, Andrei L.; Todd, Spencer C.; Pogozheva, Irina D. Protein Science, Vol. 31, Issue 1 https://doi.org/10.1002/pro.4219	journal	November 2021
Turnover Rate of the γ-Aminobutyric Acid Transporter GAT1 Gonzales, Albert L.; Lee, William; Spencer, Shelly R. Journal of Membrane Biology, Vol. 220, Issue 1-3 https://doi.org/10.1007/s00232-007-9073-5	journal	November 2007
Biomarkers of human gastrointestinal tract regions Comelli, Elena Maria; Lariani, Sofiane; Zwahlen, Marie-Camille Mammalian Genome, Vol. 20, Issue 8 https://doi.org/10.1007/s00335-009-9212-7	journal	August 2009
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
One-dimensional thin-layer chromatographic separation of lipids into fourteen fractions by two successive developments on the same plate Kovács, László; Zalka, Anna; Dobó, Rudolf Journal of Chromatography B: Biomedical Sciences and Applications, Vol. 382 https://doi.org/10.1016/S0378-4347(00)83535-5	journal	January 1986
Aromatic rescue of glycine in β sheets Merkel, Jane S.; Regan, Lynne Folding and Design, Vol. 3, Issue 6 https://doi.org/10.1016/S1359-0278(98)00062-5	journal	November 1998
Prestin's Anion Transport and Voltage-Sensing Capabilities Are Independent Bai, Jun-Ping; Surguchev, Alexei; Montoya, Simone Biophysical Journal, Vol. 96, Issue 8 https://doi.org/10.1016/j.bpj.2008.12.3948	journal	April 2009
Molecular mechanism of prestin electromotive signal amplification Ge, Jingpeng; Elferich, Johannes; Dehghani-Ghahnaviyeh, Sepehr Cell, Vol. 184, Issue 18 https://doi.org/10.1016/j.cell.2021.07.034	journal	September 2021
The SLC26 gene family of anion transporters and channels Alper, Seth L.; Sharma, Alok K. Molecular Aspects of Medicine, Vol. 34, Issue 2-3 https://doi.org/10.1016/j.mam.2012.07.009	journal	April 2013
Anion Pathways in the NarK Nitrate/Nitrite Exchanger Chon, Nara Lee; Schultz, Natalie Jean; Zheng, Hongjin Journal of Chemical Information and Modeling, Vol. 63, Issue 16 https://doi.org/10.1021/acs.jcim.3c00295	journal	August 2023
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K _a Predictions Olsson, Mats H. M.; Søndergaard, Chresten R.; Rostkowski, Michal Journal of Chemical Theory and Computation, Vol. 7, Issue 2 https://doi.org/10.1021/ct100578z	journal	December 2010
Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types Klauda, Jeffery B.; Venable, Richard M.; Freites, J. Alfredo The Journal of Physical Chemistry B, Vol. 114, Issue 23 https://doi.org/10.1021/jp101759q	journal	June 2010
Sulfation, the Up-and-Coming Post-Translational Modification: Its Role and Mechanism in Protein−Protein Interaction Woods, Amina S.; Wang, Hay-Yan J.; Jackson, Shelley N. Journal of Proteome Research, Vol. 6, Issue 3 https://doi.org/10.1021/pr060529g	journal	March 2007
Structure and mechanism of the uracil transporter UraA Lu, Feiran; Li, Shuo; Jiang, Yang Nature, Vol. 472, Issue 7342 https://doi.org/10.1038/nature09885	journal	March 2011
Crystal structure of a nitrate/nitrite exchanger Zheng, Hongjin; Wisedchaisri, Goragot; Gonen, Tamir Nature, Vol. 497, Issue 7451 https://doi.org/10.1038/nature12139	journal	May 2013
CHARMM36m: an improved force field for folded and intrinsically disordered proteins Huang, Jing; Rauscher, Sarah; Nawrocki, Grzegorz Nature Methods, Vol. 14, Issue 1 https://doi.org/10.1038/nmeth.4067	journal	November 2016
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination Punjani, Ali; Rubinstein, John L.; Fleet, David J. Nature Methods, Vol. 14, Issue 3 https://doi.org/10.1038/nmeth.4169	journal	February 2017
Structure of a prokaryotic fumarate transporter reveals the architecture of the SLC26 family Geertsma, Eric R.; Chang, Yung-Ning; Shaik, Farooque R. Nature Structural & Molecular Biology, Vol. 22, Issue 10 https://doi.org/10.1038/nsmb.3091	journal	September 2015
Structural insights into the gating mechanism of human SLC26A9 mediated by its C-terminal sequence Chi, Ximin; Jin, Xueqin; Chen, Yun Cell Discovery, Vol. 6, Issue 1 https://doi.org/10.1038/s41421-020-00193-7	journal	August 2020
Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting Okazaki, Kei-ichi; Wöhlert, David; Warnau, Judith Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-09739-0	journal	April 2019
Structure and function of an Arabidopsis thaliana sulfate transporter Wang, Lie; Chen, Kehan; Zhou, Ming Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-24778-2	journal	July 2021
Single particle cryo-EM structure of the outer hair cell motor protein prestin Butan, Carmen; Song, Qiang; Bai, Jun-Ping Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-021-27915-z	journal	January 2022
Cryo-EM structures of thermostabilized prestin provide mechanistic insights underlying outer hair cell electromotility Futamata, Haon; Fukuda, Masahiro; Umeda, Rie Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-34017-x	journal	October 2022
Highly accurate protein structure prediction with AlphaFold Jumper, John; Evans, Richard; Pritzel, Alexander Nature https://doi.org/10.1038/s41586-021-03819-2	journal	July 2021
The conformational cycle of prestin underlies outer-hair cell electromotility Bavi, Navid; Clark, Michael David; Contreras, Gustavo F. Nature, Vol. 600, Issue 7889 https://doi.org/10.1038/s41586-021-04152-4	journal	October 2021
Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs Bepler, Tristan; Morin, Andrew; Rapp, Micah Nature Methods, Vol. 16, Issue 11 https://doi.org/10.1038/s41592-019-0575-8	journal	October 2019
Measurement of atom resolvability in cryo-EM maps with Q-scores Pintilie, Grigore; Zhang, Kaiming; Su, Zhaoming Nature Methods, Vol. 17, Issue 3 https://doi.org/10.1038/s41592-020-0731-1	journal	February 2020
Engineered MATE multidrug transporters reveal two functionally distinct ion-coupling pathways in NorM from Vibrio cholerae Raturi, Sagar; Nair, Asha V.; Shinoda, Keiko Communications Biology, Vol. 4, Issue 1 https://doi.org/10.1038/s42003-021-02081-6	journal	May 2021
Solute Carrier Family 26 Member a2 (Slc26a2) Protein Functions as an Electroneutral SO42−/OH−/Cl− Exchanger Regulated by Extracellular Cl− Ohana, Ehud; Shcheynikov, Nikolay; Park, Meeyoung Journal of Biological Chemistry, Vol. 287, Issue 7 https://doi.org/10.1074/jbc.M111.297192	journal	February 2012
The Clinical Chemistry of Inorganic Sulfate Cole, David E. C.; Evrovski, Jovan Critical Reviews in Clinical Laboratory Sciences, Vol. 37, Issue 4 https://doi.org/10.1080/10408360091174231	journal	January 2000
Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells Karniski, L. P. Human Molecular Genetics, Vol. 13, Issue 19 https://doi.org/10.1093/hmg/ddh242	journal	August 2004
A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype Forlino, A. Human Molecular Genetics, Vol. 14, Issue 6 https://doi.org/10.1093/hmg/ddi079	journal	January 2005
OPM database and PPM web server: resources for positioning of proteins in membranes Lomize, Mikhail A.; Pogozheva, Irina D.; Joo, Hyeon Nucleic Acids Research, Vol. 40, Issue D1 https://doi.org/10.1093/nar/gkr703	journal	September 2011
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix Liebschner, Dorothee; Afonine, Pavel V.; Baker, Matthew L. Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 10 https://doi.org/10.1107/S2059798319011471	journal	October 2019
Clinical and molecular characterization of Diastrophic Dysplasia in the Portuguese population Barbosa, M.; Sousa, Ab; Medeira, A. Clinical Genetics, Vol. 80, Issue 6 https://doi.org/10.1111/j.1399-0004.2010.01595.x	journal	December 2010
Crystal structure of the anion exchanger domain of human erythrocyte band 3 Arakawa, Takatoshi; Kobayashi-Yurugi, Takami; Alguel, Yilmaz Science, Vol. 350, Issue 6261 https://doi.org/10.1126/science.aaa4335	journal	November 2015
Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W Ballhausen, D. Journal of Medical Genetics, Vol. 40, Issue 1 https://doi.org/10.1136/jmg.40.1.65	journal	January 2003
Shared Molecular Mechanisms of Membrane Transporters Drew, David; Boudker, Olga Annual Review of Biochemistry, Vol. 85, Issue 1 https://doi.org/10.1146/annurev-biochem-060815-014520	journal	June 2016
Regulated transport of sulfate and oxalate by SLC26A2/DTDST Heneghan, John F.; Akhavein, Arash; Salas, Maria J. American Journal of Physiology-Cell Physiology, Vol. 298, Issue 6 https://doi.org/10.1152/ajpcell.00004.2010	journal	June 2010
Physiological Roles and Regulation of Mammalian Sulfate Transporters Markovich, Daniel Physiological Reviews, Vol. 81, Issue 4 https://doi.org/10.1152/physrev.2001.81.4.1499	journal	January 2001
Epigenetic Silencing of the Sulfate Transporter Gene DTDST Induces Sialyl Lewisx Expression and Accelerates Proliferation of Colon Cancer Cells Yusa, A.; Miyazaki, K.; Kimura, N. Cancer Research, Vol. 70, Issue 10 https://doi.org/10.1158/0008-5472.CAN-09-2383	journal	May 2010
A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance Dimberg, Lina Y.; Towers, Christina G.; Behbakht, Kian Molecular Cancer Research, Vol. 15, Issue 4 https://doi.org/10.1158/1541-7786.MCR-16-0234	journal	April 2017
SLC26A2/DTDST Spectrum: A Cohort of 12 Patients Associated with a Comprehensive Review of the Genotype-Phenotype Correlation Silveira, Cynthia; da Costa Silveira, Karina; Lacarrubba-Flores, Maria D. Molecular Syndromology, Vol. 13, Issue 6 https://doi.org/10.1159/000525020	journal	January 2022
SLC26A2 (Diastrophic Dysplasia Sulfate Transporter) is Expressed in Developing and Mature Cartilage But Also in Other Tissues and Cell Types Haila, Siru; Hästbacka, Johanna; Böhling, Tom Journal of Histochemistry & Cytochemistry, Vol. 49, Issue 8 https://doi.org/10.1177/002215540104900805	journal	August 2001
MOLE 2.0: advanced approach for analysis of biomacromolecular channels Sehnal, David; Svobodová Vařeková, Radka; Berka, Karel Journal of Cheminformatics, Vol. 5, Issue 1 https://doi.org/10.1186/1758-2946-5-39	journal	August 2013
Sulfonation and Molecular Action Strott, Charles A. Endocrine Reviews, Vol. 23, Issue 5 https://doi.org/10.1210/er.2001-0040	journal	October 2002
Mechanisms of secondary structure breakers in soluble proteins Imai, Kenichiro; Mitaku, Shigeki BIOPHYSICS, Vol. 1 https://doi.org/10.2142/biophysics.1.55	journal	January 2005
Transport Turnover Rates for Human OCT2 and MATE1 Expressed in Chinese Hamster Ovary Cells Zhang, Xiaohong; Wright, Stephen H. International Journal of Molecular Sciences, Vol. 23, Issue 3 https://doi.org/10.3390/ijms23031472	journal	January 2022
Cryo-EM structures and functional characterization of murine Slc26a9 reveal mechanism of uncoupled chloride transport Walter, Justin D.; Sawicka, Marta; Dutzler, Raimund eLife, Vol. 8 https://doi.org/10.7554/eLife.46986	journal	July 2019

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Title: Substrate binding plasticity revealed by Cryo-EM structures of SLC26A2

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