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Reconstructing the transport cycle in the sugar porter superfamily using coevolution-powered machine learning
Darko Mitrovic1, Sarah E McComas1,2, Claudia Alleva1,2
1Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
Elife
|July 5, 2023
Summary
Researchers developed a computational method to predict sugar transporter structures and transport mechanisms. This approach models the entire sugar porter superfamily, offering insights into glucose transporter function and cancer-related research.
Area of Science:
- Structural biology
- Computational biophysics
- Molecular transport mechanisms
Background:
- Sugar porters (SPs) are crucial secondary-active transporters, including glucose transporters (GLUTs), vital for blood glucose homeostasis.
- GLUTs are implicated in various cancers, yet their transport mechanisms are poorly understood due to limited structural data.
- Existing GLUT transport models are often oversimplified and lack mechanistic detail.
Purpose of the Study:
- To predict structures of the entire sugar porter superfamily across different transport cycle states.
- To elucidate conserved molecular determinants governing the sugar transport cycle.
- To refine and extend existing models of transporter function, such as the latch mechanism.
Main Methods:
- Combined coevolution analysis with comparative modeling to predict protein structures.
- Analyzed state-specific contacts derived from coevolving residue pairs.
- Generated free-energy landscapes for transporters, exemplified by the GLUT5 transporter.
Main Results:
- Generated predictive structural models for the sugar porter superfamily in various transport states.
- Identified conserved molecular determinants of the transport cycle across SPs.
- Highlighted variations leading to proton-coupling and validated the latch mechanism.
Conclusions:
- The developed computational approach accurately models sugar transporter mechanisms and structures.
- This method provides a framework for understanding conserved and divergent transport functions within the superfamily.
- The approach is broadly applicable to other transporter families and proteins.
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