Structural basis for multivitamin recognition and transport by human SMVT

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Transport

Background:

• The human sodium-dependent multivitamin transporter (SMVT, SLC5A6) is crucial for cellular uptake of vital cofactors like biotin.
• SMVT dysfunction is linked to neurological disorders, metabolic issues, and cancer, yet its transport mechanism remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism of human SMVT's multi-substrate transport.
• To provide high-resolution structural insights into the complete transport cycle of SMVT.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine structures of SMVT in three distinct conformational states.
• Functional assays to identify key substrate-binding residues and assess disease-associated mutations.

Main Results:

• Determined cryo-EM structures of SMVT capturing occluded, outward-open, and inward-open states, visualizing the entire transport cycle.
• Identified a conserved substrate-binding pocket with specific interactions for biotin, pantothenate, and lipoate.
• Elucidated the roles of key residues in substrate binding and discrimination, and the impact of disease-linked mutations.

Conclusions:

• The study provides a detailed structural framework for SMVT's polyspecificity and transport mechanism.
• Findings offer insights into the molecular basis of SMVT-related diseases.
• This work lays the groundwork for developing targeted therapeutic strategies for SMVT-associated conditions.