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Structural basis for LMBD1-dependent trafficking and cobalamin export of ABCD4.
Qiwei Liu1, Xingfan Li1, Yingjie Wu1
1State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Medical School (School of Basic Medical Sciences), Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
Nature Communications
|June 16, 2026
Summary
Lysosomal transporter ABCD4 relies on chaperone LMBD1 for correct trafficking, crucial for cobalamin metabolism. Structural studies reveal how LMBD1 facilitates ABCD4 transport, offering insights into inherited disorders.
Area of Science:
- Cell Biology
- Structural Biology
- Biochemistry
Background:
- Lysosomal transporters require precise trafficking for cellular homeostasis.
- ABCD4, a cobalamin exporter, uniquely depends on the chaperone LMBD1 for lysosomal delivery.
- Defects in ABCD4 or LMBD1 lead to inherited cobalamin metabolism disorders.
Purpose of the Study:
- To elucidate the molecular mechanism of LMBD1-mediated trafficking of ABCD4.
- To determine the structural basis of cobalamin recognition and transport by the ABCD4-LMBD1 complex.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine structures of ABCD4-LMBD1 complex.
- Biochemical assays to analyze protein interactions and cobalamin binding.
- Cell imaging to assess the impact of disrupted interactions on lysosomal trafficking.
Main Results:
- Determined cryo-EM structures of ABCD4 complexed with LMBD1 in multiple functional states (lumen-open, substrate-bound, cytosol-open).
- Identified interactions between LMBD1's transmembrane helices and cytosolic domain with ABCD4.
- Demonstrated that disruption of these interactions impairs ABCD4 lysosomal trafficking.
- Provided insights into cobalamin binding and the conformational changes during transport.
Conclusions:
- LMBD1 acts as a dedicated chaperone, utilizing specific interactions to facilitate ABCD4 lysosomal transport.
- The study reveals the structural dynamics of the cobalamin transport cycle.
- Findings illuminate the molecular basis of inherited cobalamin metabolism disorders and highlight a novel chaperone-assisted trafficking mechanism for lysosomal transporters.
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