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Bioengineer
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Human SLC35B1 Powers Stepwise ATP ER Transport
- Recent research has identified human SLC35B1 as the key transporter for ATP entry into the ER, a groundbreaking discovery after three decades of investigation.
- SLC35B1 differs from other transporters in substrate specificity, efficiently transporting ADP and ATP to support the ER's energy-demanding processes.
- This finding is crucial for understanding intracellular nucleotide trafficking, especially in maintaining ER homeostasis during cellular stress.
- Structurally, SLC35B1 features a unique substrate cavity that accommodates ATP molecules in a bent conformation, requiring a stepwise translocation strategy for transport.
- The transporter's mechanism involves ATP binding to specific regions, such as hydrophobic patch interactions and ligand repositioning facilitated by gating helices.
- SLC35B1's transport cycle includes vertical displacement of the ATP molecule and conformational shifts in gating helices for controlled translocation across the ER membrane.
- The transporter exhibits complex intermediates in its transport cycle, suggesting a sophisticated mechanism similar to mitochondrial carriers for nucleotide movement.
- The discovery of SLC35B1 raises questions about regulating nucleotide supply during cellular energy fluctuations and its potential implications for ER stress-related diseases.
- Understanding SLC35B1 could offer insights into maintaining proteostasis, regulating energy distribution, and exploring therapeutic targets for ER stress-related disorders.
- By integrating cryo-electron microscopy, biochemical kinetics, and genetic perturbation, this research provides a dynamic mechanistic model for transporter function at atomic resolution.
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