Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

5.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
5.2K
Conserved Binding Sites01:49

Conserved Binding Sites

2.0K
2.0K
Ligand Binding Sites02:40

Ligand Binding Sites

15.2K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
15.2K
Ligand Binding Sites02:40

Ligand Binding Sites

8.9K
8.9K
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

8.9K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
8.9K
Non-gated Ion Channels01:24

Non-gated Ion Channels

8.3K
Ion channels are specialized proteins on the plasma membrane that allow charged ions to pass down their electrochemical gradient. Their main function is to maintain the membrane potential which is critical for cell viability. These channels are either gated or non-gated and can transport more than a thousand ions within milliseconds for the cellular event to occur.
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism....
8.3K

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

PIP <sub>2</sub> stabilizes Na <sub>V</sub> 1.5 gating and links receptor signaling to cardiac late sodium current.

bioRxiv : the preprint server for biology·2026
Same author

PfApiAT2 is a proline transporter essential for the transmission of Plasmodium falciparum by the mosquito vector.

Nature communications·2026
Same author

Ion Channel Nano-Diagnostics for ER+ Breast Cancer.

bioRxiv : the preprint server for biology·2026
Same author

PfApiAT2 is a proline transporter essential for the transmission of <i>Plasmodium falciparum</i> by the mosquito vector.

Research square·2026
Same author

PfApiAT2 is a proline transporter essential for the transmission of <i>Plasmodium falciparum</i> by the mosquito vector.

bioRxiv : the preprint server for biology·2026
Same author

Understanding Ion Channel Gating Mechanisms by Molecular Dynamics Simulations.

Advances in experimental medicine and biology·2026

Related Experiment Video

Updated: Feb 12, 2026

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
11:34

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins

Published on: August 9, 2019

7.1K

Allosteric coupling between PIP2 and Ca2+ binding sites gates TMEM16A channels.

Jie Xu1,2,3, Ana Santa-Cruz1,2, Aishwarya Chandrashekar1,2

  • 1Department of Pharmaceutical Sciences, Center for Drug Discovery, School of Pharmacy and Pharmaceutical Sciences, Bouve College of Health Science, Northeastern University, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|February 10, 2026
PubMed
Summary

Phosphatidylinositol 4,5-bisphosphate (PIP2) and calcium (Ca2+) cooperatively gate TMEM16A channels. PIP2 headgroups and acyl chains, along with Ca2+, are essential for TMEM16A channel activation and function.

Keywords:
PIP2TMEM16Aion permeationmolecular dynamics

More Related Videos

PAR-CliP - A Method to Identify Transcriptome-wide the Binding Sites of RNA Binding Proteins
12:24

PAR-CliP - A Method to Identify Transcriptome-wide the Binding Sites of RNA Binding Proteins

Published on: July 2, 2010

54.2K
Biocytin Recovery and 3D Reconstructions of Filled Hippocampal CA2 Interneurons
11:21

Biocytin Recovery and 3D Reconstructions of Filled Hippocampal CA2 Interneurons

Published on: November 20, 2018

9.0K

Related Experiment Videos

Last Updated: Feb 12, 2026

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
11:34

Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins

Published on: August 9, 2019

7.1K
PAR-CliP - A Method to Identify Transcriptome-wide the Binding Sites of RNA Binding Proteins
12:24

PAR-CliP - A Method to Identify Transcriptome-wide the Binding Sites of RNA Binding Proteins

Published on: July 2, 2010

54.2K
Biocytin Recovery and 3D Reconstructions of Filled Hippocampal CA2 Interneurons
11:21

Biocytin Recovery and 3D Reconstructions of Filled Hippocampal CA2 Interneurons

Published on: November 20, 2018

9.0K

Area of Science:

  • Ion channel biophysics
  • Molecular physiology
  • Membrane protein structure and function

Background:

  • TMEM16A channels are crucial for physiological processes like secretion and muscle contraction.
  • Channel activation depends on both intracellular calcium (Ca2+) and the signaling phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2).
  • The precise molecular mechanism of this dual regulation remained elusive.

Purpose of the Study:

  • To elucidate the molecular basis of Ca2+ and PIP2 cooperative gating in TMEM16A channels.
  • To investigate the specific roles of PIP2 headgroup and acyl chain interactions in channel activation.
  • To understand the interplay between lipid binding and ion permeation.

Main Methods:

  • Gating molecular-dynamics simulations.
  • Structure-guided electrophysiology.
  • Analysis of lipid-protein interactions at the molecular level.

Main Results:

  • PIP2 and Ca2+ cooperatively gate TMEM16A via an allosterically coupled electrostatic network involving the α4 helix.
  • PIP2 headgroup phosphates link Ca2+ binding to channel opening.
  • PIP2 acyl chains stabilize the open state by engaging hydrophobic surfaces.
  • Disrupting PIP2 interactions impairs activation, while specific PIP2 variants restore function.

Conclusions:

  • Both PIP2 headgroup phosphates and acyl chains play critical, complementary roles in TMEM16A gating.
  • A cooperative lipid-ion activation mechanism governs TMEM16A function.
  • This mechanism provides a framework for understanding phosphoinositide regulation of ion channels.
  • Findings offer insights for structure-based design of TMEM16A modulators.