Cryo-EM structures and functional characterization of the murine lipid scramblase TMEM16F

Area of Science:

• Structural Biology
• Biochemistry
• Membrane Protein Function

Background:

• The TMEM16F protein is a key regulator of blood coagulation, initiating the process by exposing phosphatidylserine on platelets.
• TMEM16F belongs to a family of membrane proteins with known calcium-activated ion and lipid channel activity.

Purpose of the Study:

• To elucidate the structural features of murine TMEM16F (mTMEM16F) responsible for its dual lipid scramblase and ion channel functions.
• To understand the relationship between ion conduction and lipid scrambling mechanisms within TMEM16F.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structures of mTMEM16F in ligand-free closed and Ca2+-bound intermediate states.
• Functional data were integrated with structural findings to correlate ion conduction with lipid scrambling activity.

Main Results:

• Cryo-EM revealed distinct conformations of mTMEM16F, including a ligand-free closed state and a Ca2+-bound intermediate.
• These conformations share similarities with the anion channel mTMEM16A but exhibit unique differences in ion and lipid permeation pathways.
• Functional data confirmed a link between ion conduction and lipid scrambling, suggesting they are mediated by alternate protein conformations.

Conclusions:

• Murine TMEM16F possesses distinct structural conformations that enable its functions as both a lipid scramblase and an ion channel.
• While activated by a common mechanism, ion conduction and lipid scrambling are likely governed by alternative protein states in equilibrium.
• The findings provide insights into the molecular basis of TMEM16F's role in blood coagulation and membrane transport.