Cryo-EM Structures Reveal Lipid-Lined Pore Formation in Mechanosensitive OSCA Ion Channels

Centrala begrepp

Mechanical activation induces a lipid-lined pore formation in OSCA/TMEM63 mechanosensitive ion channels, which play critical roles in plant and mammalian mechanotransduction.

Sammanfattning

The article presents a comprehensive structural and functional analysis of the OSCA/TMEM63 family of mechanosensitive ion channels using cryogenic electron microscopy (cryo-EM). OSCA/TMEM63 channels are the largest known family of mechanosensitive channels and play crucial roles in plant and mammalian mechanotransduction.

The key findings are:

1. In nanodiscs mimicking increased membrane tension, the OSCA1.2 channel exhibits a dilated pore with membrane access in one of the subunits.
2. In liposomes, the fully open structure of OSCA1.2 in the inside-in orientation shows a large lateral opening to the membrane, forming a 'proteo-lipidic pore' where lipids act as a wall of the ion permeation pathway.
3. In the less tension-sensitive homologue OSCA3.1, a tightly bound 'interlocking' lipid in the central cleft keeps the channel closed. Mutating the lipid-coordinating residues activates OSCA3.1, revealing a conserved open conformation of OSCA channels.
4. The structures provide a comprehensive understanding of the OSCA channel gating cycle, highlighting the importance of bound lipids and the ability of each subunit to open independently.
5. These findings expand our knowledge of channel-mediated mechanotransduction and pore formation, with implications for the TMEM16 and TMC protein families.

Statistik

OSCA/TMEM63 channels are the largest known family of mechanosensitive channels.
Cryo-EM structures of OSCA/TMEM63 channels in different environments were determined.
The OSCA1.2 channel exhibits a dilated pore with membrane access in one subunit under increased membrane tension.
The fully open structure of OSCA1.2 in liposomes shows a large lateral opening to the membrane, forming a 'proteo-lipidic pore'.
In OSCA3.1, a tightly bound 'interlocking' lipid in the central cleft keeps the channel closed.
Mutating the lipid-coordinating residues activates OSCA3.1, revealing a conserved open conformation of OSCA channels.

Citat

"Structural, functional and computational evidence supports the existence of a 'proteo-lipidic pore' in which lipids act as a wall of the ion permeation pathway."
"Our structures provide a global picture of the OSCA channel gating cycle, uncover the importance of bound lipids and show that each subunit can open independently."

Viktiga insikter från

Mechanical activation opens a lipid-lined pore in OSCA ion channels - Nature

by Yaoyao Han,Z... på www.nature.com 04-03-2024

https://www.nature.com/articles/s41586-024-07256-9

Djupare frågor

How do the structural features and gating mechanisms of OSCA/TMEM63 channels compare to other mechanosensitive ion channel families, such as Piezo and MscS?

The structural features and gating mechanisms of OSCA/TMEM63 channels exhibit unique characteristics compared to other mechanosensitive ion channel families like Piezo and MscS. OSCA channels, as revealed by cryogenic electron microscopy structures, display a 'proteo-lipidic pore' architecture where lipids play a crucial role in forming the ion permeation pathway. This differs from the more traditional protein-lined pores seen in other ion channels. Additionally, OSCA channels show a conserved open conformation across different subunits, allowing for independent opening of each subunit. In contrast, Piezo channels are known for their large size and unique trimeric structure, while MscS channels have a distinct gating mechanism involving a large cytoplasmic domain that acts as a mechanical spring. These differences highlight the diverse structural and functional adaptations that have evolved in mechanosensitive ion channels to respond to mechanical stimuli.

What are the potential physiological implications of the 'proteo-lipidic pore' architecture in OSCA/TMEM63 channels, and how might it influence their role in mechanotransduction?

The 'proteo-lipidic pore' architecture in OSCA/TMEM63 channels has significant physiological implications for their role in mechanotransduction. By incorporating lipids as an integral part of the ion permeation pathway, OSCA channels may be more sensitive to changes in membrane tension and lipid composition. This unique architecture could allow for fine-tuning of channel activity in response to mechanical stimuli, providing a mechanism for cells to sense and respond to their mechanical environment. The presence of lipid-coordinating residues that regulate channel activation suggests that lipid-protein interactions play a crucial role in modulating OSCA channel function. Understanding how the 'proteo-lipidic pore' influences mechanotransduction could shed light on how cells sense and transduce mechanical signals, impacting processes such as cell migration, tissue development, and sensory perception.

Could the insights into OSCA channel activation through lipid-coordinating residue mutations be leveraged to develop novel therapeutic strategies for mechanosensitive ion channel-related diseases?

The insights gained from studying OSCA channel activation through lipid-coordinating residue mutations hold promise for the development of novel therapeutic strategies for mechanosensitive ion channel-related diseases. Targeting the lipid-protein interactions that regulate OSCA channel activity could offer a new avenue for modulating mechanotransduction pathways in various physiological and pathological conditions. By understanding how specific mutations in lipid-coordinating residues lead to channel activation, researchers may be able to design small molecules or peptides that mimic or disrupt these interactions, thereby modulating channel function. This approach could be particularly relevant for diseases involving aberrant mechanosensitive ion channel activity, such as certain types of cardiac arrhythmias, hearing loss, or cancer metastasis. Leveraging the mechanistic insights from OSCA channels could pave the way for innovative therapeutic interventions targeting mechanosensitive ion channels.