Atomistic insight into lipid translocation by a TMEM16 scramblase

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• The TMEM16 family comprises proteins with diverse functions, including lipid scrambling and ion channel activity.
• Understanding the mechanism of lipid transport is crucial for elucidating TMEM16 protein functions in olfaction, nociception, and coagulation.

Purpose of the Study:

• To computationally investigate the membrane-protein interactions driving lipid scrambling in the TMEM16 family.
• To explore the role of membrane bending and specific residue interactions in facilitating lipid headgroup movement.

Main Methods:

• Utilized continuum membrane-bending calculations to analyze large-scale membrane deformation.
• Employed atomic simulations to identify lipid headgroup interaction sites within the protein.
• Performed homology modeling on mammalian TMEM16 proteins.

Main Results:

• Identified a pattern of charged and hydrophobic residues that induce significant membrane bending and thinning.
• Discovered two key lipid headgroup interaction sites flanking the transport groove.
• Observed direct lipid molecule translocation across the bilayer through the identified groove and interaction sites.
• Demonstrated that even non-scramblase TMEM16 homologs induce membrane bending.

Conclusions:

• Large-scale membrane bending, driven by specific protein residues, is a key mechanism for lipid permeation in TMEM16 proteins.
• Conserved lipid-interaction sites suggest a shared mechanistic basis for lipid transport across the TMEM16 family.
• Hypothesize that membrane interaction modulation may also influence TMEM16 ion channel activity.