The STIM-Orai Pathway: STIM-Orai Structures: Isolated and in Complex

Area of Science:

• Molecular biology
• Structural biology
• Cellular physiology

Background:

• Stromal interaction molecules (STIMs) and Orai channels are crucial for store-operated calcium entry (SOCE).
• Elucidating their molecular mechanisms is key to understanding calcium (Ca2+) signaling.
• Recent advances provide high-resolution structural details of these proteins.

Purpose of the Study:

• To review and discuss available high-resolution structural data of STIM and Orai proteins.
• To explore the structural basis for the regulation of SOCE.
• To correlate structural findings with functional observations.

Main Methods:

• Review of solution structures of STIM1 and STIM2 Ca2+-sensing domains.
• Discussion of crystal structures of STIM cytosolic coiled-coil fragments.
• Overview of the closed Drosophila melanogaster Orai hexameric structure.
• Highlighting structures of human Orai1 domains in complex with calmodulin and STIM1.

Main Results:

• Detailed structural information on STIM Ca2+-sensing domains and cytosolic fragments is available.
• The closed hexameric structure of Drosophila Orai provides insights into channel gating.
• Structures of human Orai1 domains complexed with calmodulin and STIM1 offer mechanistic clues.

Conclusions:

• Accessible structural data for STIM and Orai proteins are crucial for understanding SOCE regulation.
• Structural information supports potential mechanisms of action for STIM and Orai in calcium signaling.
• Cohesiveness between structural data and functional observations strengthens mechanistic models of SOCE.