Store-operated Orai channels: structure and function

Area of Science:

• Cellular Biology
• Molecular Physiology

Background:

• Store-operated calcium (Ca2+) release-activated Ca2+ (CRAC) channels are critical for numerous cellular processes, including gene expression, motility, and proliferation.
• Dysfunction of CRAC channels is implicated in diseases such as severe combined immunodeficiency syndrome, highlighting their therapeutic potential.
• Decades of research have elucidated the fundamental roles of CRAC channels, yet their precise molecular mechanisms remained elusive until recent discoveries.

Purpose of the Study:

• To review the molecular mechanisms governing the operation and function of CRAC channels.
• To highlight the roles of STIM1 and Orai1 proteins in CRAC channel regulation.
• To discuss the structural features of STIM and Orai proteins that control CRAC channel gating and ion conduction.

Main Methods:

• Review of existing literature on CRAC channel function and molecular mechanisms.
• Focus on the discovery and characterization of Orai1 and STIM1 proteins.
• Analysis of protein-protein interactions and cellular redistribution events.

Main Results:

• The discovery of Orai1 and STIM1 has significantly advanced the understanding of CRAC channel operation.
• CRAC channel activation involves the redistribution of STIM1 and Orai1 to peripheral sites upon endoplasmic reticulum (ER) Ca2+ store depletion.
• Direct protein-protein interactions between STIM1 and Orai1 are essential for CRAC channel gating.

Conclusions:

• STIM1 and Orai1 are key regulators of CRAC channel activity.
• Understanding the molecular interplay between STIM1 and Orai1 provides insights into CRAC channel function and disease.
• Further investigation into the molecular features of STIM and Orai proteins can inform drug development for CRAC channel-related disorders.