Mobile barrier mechanisms for Na+-coupled symport in an MFS sugar transporter
Open accessPreprint — published as 10.7554/elife.92462.3 · Paper page
Abstract
Abstract While many 3D structures of cation-coupled transporters have been determined, the mechanistic details governing the obligatory coupling and functional regulations still remain elusive. The bacterial melibiose transporter (MelB) is a prototype of the Na+-coupled major facilitator superfamily transporters. With a conformational nanobody (Nb), we determined a low-sugar affinity inward-facing Na+-bound cryoEM structure. Collectively with the available outward-facing sugar-bound structures, both the outer and inner barriers were localized. The N-and C-terminal residues of the inner barrier contribute to the sugar selectivity pocket. When the inner barrier is broken as shown in the inward-open conformation, the sugar selectivity pocket is also broken. The binding assays by isothermal titration calorimetry revealed that this inward-facing conformation trapped by the conformation-selective Nb exhibited a greatly decreased sugar-binding affinity, suggesting the mechanisms for the substrate intracellular release and accumulation. While the inner/outer barrier shift directly regulates the sugar-binding affinity, it has little or no effect on the cation binding, which is also supported by molecular dynamics simulations. Furthermore, the use of this Nb in combination with the hydron/deuterium exchange mass spectrometry allowed us to identify dynamic regions; some regions are involved in the functionally important inner barrier-specific salt-bridge network, which indicates their critical roles in the barrier switching mechanisms for transport. These complementary results provided structural and dynamic insights into the mobile barrier mechanism for cation-coupled symport.
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- Hariharan, P., Shi, Y., Katsube, S., Willibal, K., Burrows, N. D., Mitchell, P., Bakhtiiari, A., Stanfield, S., Pardon, E., Kaback, H. R., Liang, R., Steyaert, J., Viner, R., & Guan, L.
- Affiliations
- Texas Tech University (US)
- Thermo Fisher Scientific (United States) (US)
- VIB-VUB Center for Structural Biology (BE)
- SLAC National Accelerator Laboratory (US)
- Department of Physiology, University of California
- ORCID
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- eLife
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- eLife Sciences Publications, Ltd
- Published
- 2024-01-25
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- 2050-084X (ISSN-L)
- OpenAlex
- W4391229982
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- Funders
- National Institute of General Medical Sciences (R01 GM122759)
- Welch Foundation (D-2108-20220331)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- major facilitator superfamily, MelB, inward-facing conformation, salt bridge network, cation binding, substrate release
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