Preprint

FZJ-2024-06005

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters

Dmitrieva, N.FZJ* ; Gholami, S.FZJ* ; Alleva, C. ; Carloni, P.FZJ* ; Alfonso-Prieto, M. (Corresponding author)FZJ* ; Fahlke, C. (Corresponding author)FZJ*

2024
Wiley Hoboken, NJ [u.a.]

Abstract: The solute carrier 17 (SLC17) family contains anion transportersthat accumulate neurotransmitters in secretory vesicles, removecarboxylated monosaccharides from lysosomes, or extrude organicanions from the kidneys and liver.We combined classical moleculardynamics simulations, Markov state modeling and hybrid firstprinciples quantum mechanical/classical mechanical (QM/MM)simulations with experimental approaches to describe the transportmechanisms of a model bacterial protein, the D-galactonatetransporter DgoT, at atomic resolution. We found that protonationof D46 and E133 precedes galactonate binding and that substratebinding induces closure of the extracellular gate, with the conservedR47 coupling substrate binding to transmembrane helixmovement. After isomerization to an inward-facing conformation,deprotonation of E133 and subsequent proton transfer from D46 toE133 opens the intracellular gate and permits galactonate dissociationeither in its unprotonated form or after proton transferfrom E133. After release of the second proton, apo DgoT returns tothe outward-facing conformation. Our results provide a frameworkto understand how various SLC17 transport functions with distincttransport stoichiometries can be attained through subtle variationsin proton and substrate binding/unbinding.

Note: We thank Drs Andre Bazzone, Bassam Haddad, Andrei Kostritskii, PiersilvioLongo and Jan-Philipp Machtens for helpful discussions and Meike Berndt forexcellent technical support. This work was supported by the DeutscheForschungsgemeinschaft (German Research Foundation) to ChF (FA 301/15–2), PC (CA 973/27-2) and MAP (AL 2511/1-2) as part of Research Unit FOR2518, DynIon. The authors gratefully acknowledge computing time on the supercomputer JURECA at Forschungszentrum Jülich under grants dgoth and vglut-pt.Open Access article as part of the DEAL agreement with Wiley.

---

Contributing Institute(s):

1. Molekular- und Zellphysiologie (IBI-1)
2. Computational Biomedicine (INM-9)

Research Program(s):

1. 5243 - Information Processing in Distributed Systems (POF4-524) (POF4-524)
2. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)
3. DFG project G:(GEPRIS)426950122 - FOR 5046: Integrative Analyse epithelialer SLC26 Anionentransporter – von der molekularen Struktur zur Pathophysiologie (426950122) (426950122)
4. DFG project G:(GEPRIS)291198853 - FOR 2518: Funktionale Dynamik von Ionenkanälen und Transportern - DynIon - (291198853) (291198853)
5. DFG project G:(GEPRIS)329460521 - Protonentransfer und Substraterkennung in SLC17-Transportern (329460521) (329460521)

Appears in the scientific report 2024

---

Database coverage:
; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---