Membrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins
[1]
- Department of Physiology and Biophysics Weill Cornell Medical College of Cornell University New York New York 10065, Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University New York New York 10065
- Department of Physiology and Biophysics Weill Cornell Medical College of Cornell University New York New York 10065
- Department of Biochemistry Weill Cornell Medical College of Cornell University New York New York 10065
- Department of Integrative Biology and Pharmacology University of Texas Health Science Center at Houston Houston Texas 77030
- Department of Physiology and Biophysics Weill Cornell Medical College of Cornell University New York New York 10065, Department of Biochemistry Weill Cornell Medical College of Cornell University New York New York 10065, Department of Anesthesiology Weill Cornell Medical College of Cornell University New York New York 10065
Recent discoveries about functional mechanisms of proteins in the TMEM16 family of phospholipid scramblases have illuminated the dual role of the membrane as both the substrate and a mechanistically responsive environment in the wide range of physiological processes and genetic disorders in which they are implicated. This is highlighted in the review of recent findings from our collaborative investigations of molecular mechanisms of TMEM16 scramblases that emerged from iterative functional, structural, and computational experimentation. In the context of this review, we present new MD simulations and trajectory analyses motivated by the fact that new structural information about the TMEM16 scramblases is emerging from cryo‐EM determinations in lipid nanodiscs. Because the functional environment of these proteins in in vivo and in in vitro is closer to flat membranes, we studied comparatively the responses of the membrane to the TMEM16 proteins in flat membranes and nanodiscs. We find that bilayer shapes in the nanodiscs are very different from those observed in the flat membrane systems, but the function‐related slanting of the membrane observed at the nhTMEM16 boundary with the protein is similar in the nanodiscs and in the flat bilayers. This changes, however, in the bilayer composed of longer‐tail lipids, which is thicker near the phospholipid translocation pathway, which may reflect an enhanced tendency of the long tails to penetrate the pathway and create, as shown previously, a nonconductive environment. These findings support the correspondence between the mechanistic involvement of the lipid environment in the flat membranes, and the nanodiscs. © 2019 Wiley Periodicals, Inc.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1575104
- Journal Information:
- Journal of Computational Chemistry, Journal Name: Journal of Computational Chemistry Vol. 41 Journal Issue: 6; ISSN 0192-8651
- Publisher:
- Wiley Blackwell (John Wiley & Sons)Copyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
Similar Records
The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase
Light-independent phospholipid scramblase activity of bacteriorhodopsin from Halobacterium salinarum