# Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $415,275

## Abstract

Members of the TMEM16 family of integral membrane proteins are Ca2+-dependent phospholipid scramblases.
Because mechanisms of lipid scrambling by the TMEM16s remain poorly understood, the ability to interpret
their function in human physiology and to design targeted pharmacological interventions that would selectively
manipulate the activity of these proteins, is limited. Our goal is to overcome these limitations by determining
how the TMEM16 scramblases are activated in response to Ca2+ binding, how and for what purpose they
remodel cellular membranes, and how they are affected by specific components of these membranes. We
address this mechanistic goal with an integrated strategy combining experimentation with structural, functional,
and computational approaches. To understand how these proteins are modulated in vivo we will focus on
ceramides as the first class of molecules found to inhibit the function of TMEM16 scramblases and to be
associated in vivo with excessive exposure of PS in endothelial cells. Our 1st aim is to determine the Ca2+-
dependent gating mechanism of the TMEM16 scramblases using a combination of cryo-electron microscopy
(cryoEM), molecular dynamics (MD) simulations and functional assays. These experiments will reveal the
allosteric coupling mechanism between the Ca2+ binding site and the structural elements gating the lipid
pathway. Our 2nd aim is to determine how the TMEM16 scramblases interact with, and alter the structure of,
their surrounding membrane environment in support of their function. Using structure determination with
cryoEM we will visualize afTMEM16 complexes with membranes with a variety of physicochemical properties
and compositions, in different functional states. In combination with MD simulations and functional assays we
will identify the energetic and molecular determinants for membrane-protein interactions and membrane
remodeling, and their role in scrambling. Our 3rd aim is to determine the mechanism and in vivo role of
ceramide regulation of TMEM16 scramblases using functional assays to identify the molecular determinants of
ceramide inhibition, and structural and computational experiments to determine their mechanism of action, and
the role of specific ceramides in the in vivo regulation of TMEM16F.

## Key facts

- **NIH application ID:** 10170367
- **Project number:** 5R01GM106717-07
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Alessio Accardi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,275
- **Award type:** 5
- **Project period:** 2014-06-04 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170367

## Citation

> US National Institutes of Health, RePORTER application 10170367, Ca2+-dependent lipid scrambling and ion transport by TMEM16 proteins (5R01GM106717-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10170367. Licensed CC0.

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