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Structural basis for functional interactions in dimers of SLC26 transporters.

ABSTRACT: The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7?+?7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by combining PELDOR/DEER distance measurements and biochemical studies with MD simulations and spin-label ensemble refinement. Our structural model reveals a unique interface different from the SLC4 and SLC23 families. The functionally relevant STAS domain is no prerequisite for dimerization. Characterization of heterodimers indicates that protomers in the dimer functionally interact. The combined structural and functional data define the framework for a mechanistic understanding of functional cooperativity in SLC26 dimers.

SUBMITTER: Chang YN

PROVIDER: S-EPMC6497670 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Structural basis for functional interactions in dimers of SLC26 transporters.

Chang Yung-Ning YN Jaumann Eva A EA Reichel Katrin K Hartmann Julia J Oliver Dominik D Hummer Gerhard G Joseph Benesh B Geertsma Eric R ER

Nature communications 20190502 1

The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. The family shares a 7 + 7 transmembrane segments inverted repeat architecture with the SLC4 and SLC23 families, but holds a regulatory STAS domain in addition. While the only experimental SLC26 structure is monomeric, SLC26 proteins form structural and functional dimers in the lipid membrane. Here we resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize its functional relevance by ...[more]

PMID: 31048734

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Project description:Vinblastine and its derivatives used in clinics as antitumor drugs often cause drug resistance and some serious side effects; thus, it is necessary to study new vinblastine analogues with strong anticancer cytotoxicity and low toxicity. We designed a dimer molecule using two vindoline-bonded dimer vindoline (DVB) and studied its interaction with α,β-tubulin through the double-sided adhesive mechanism to explore its anticancer cytotoxicity. In our work, DVB was docked into the interface between α-tubulin and β-tubulin to construct a complex protein structure, and then it was simulated for 100 ns using the molecular dynamics technology to become a stable and refined complex protein structure. Based on such a refined structure, the quantum chemistry at the level of the MP2/6-31G(d,p) method was used to calculate the binding energies for DVB interacting with respective residues. By the obtained binding energies, the active site residues for interaction with DVB were found. Up to 20 active sites of residues within α,β-tubulin interacting with DVB are labeled in β-Asp179, β-Glu207, β-Tyr210, β-Asp211, β-Phe214, β-Pro222, β-Tyr224, and β-Leu227 and α-Asn249, α-Arg308, α-Lys326, α-Asn329, α-Ala333, α-Thr334, α-Lys336, α-Lys338, α-Arg339, α-Ser340, α-Thr349, and α-Phe351. The total binding energy between DVB and α,β-tubulin is about -251.0 kJ·mol-1. The sampling average force potential (PMF) method was further used to study the dissociation free energy (ΔG) along the separation trajectory of α,β-tubulin under the presence of DVB based on the refined structure of DVB with α,β-tubulin. Because of the presence of DVB within the interface between α- and β-tubulin, ΔG is 252.3 kJ·mol-1. In contrast to the absence of DVB, the separation of pure β-tubulin needs a free energy of 196.9 kJ·mol-1. The data show that the presence of DVB adds more 55.4 kJ·mol-1 of ΔG to hinder the normal separation of α,β-tubulin. Compared to vinblastine existing, the free energy required for the separation of α,β-tubulin is 220.5 kJ·mol-1. Vinblastine and DVB can both be considered through the same double-sided adhesive mechanism to give anticancer cytotoxicity. Because of the presence of DVB, a larger free energy is needed for the separation of α,β-tubulin, which suggests that DVB should have stronger anticancer cytotoxicity than vinblastine and shows that DVB has a broad application prospect.

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Structural basis for functional interactions in dimers of SLC26 transporters.

Publications

Structural basis for functional interactions in dimers of SLC26 transporters.

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