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Cryo-EM Studies of TMEM16F Calcium-Activated Ion Channel Suggest Features Important for Lipid Scrambling
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Jul 09 2019
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Source: Cell Rep. 28(2):567-579.e4
[PDF-3.44 MB]
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Alternative Title:Cell Rep
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Description:As a Ca|-activated lipid scramblase and ion channel that mediates Ca| influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP|-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca| influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest separate pathways for lipid scrambling and ion permeation.
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Pubmed ID:31291589
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Pubmed Central ID:PMC6684876
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Funding:S10 OD021741/ODCDC CDC HHS/Office of the Director/United States ; R01 NS069229/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United States ; S10 OD020054/ODCDC CDC HHS/Office of the Director/United States ; R56 NS097229/NINDS NIH HHS/National Institute of Neurological Disorders and Stroke/United States ; R01 GM098672/NIGMS NIH HHS/National Institute of General Medical Sciences/United States
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Volume:28
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Issue:2
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