Molecular evolution and structural analysis of the Ca(2+) release-activated Ca(2+) channel subunit, Orai

Area of Science:

• Molecular Biology
• Evolutionary Biology
• Biochemistry

Background:

• Intracellular Ca(2+) store depletion triggers Ca(2+) influx via Ca(2+) release-activated Ca(2+) (CRAC) channels.
• Orai and STIM proteins are the identified molecular components of CRAC channels and ER Ca(2+) sensors, respectively.
• Mammalian Orai proteins exhibit diverse functional properties, suggesting evolutionary divergence.

Purpose of the Study:

• To investigate the evolutionary origins and diversification of Orai proteins.
• To identify potential ancestral Orai sequences and track the acquisition of structural domains.
• To correlate evolutionary patterns with functional differences in CRAC currents across species.

Main Methods:

• Extensive database searching and phylogenetic analysis of Orai protein sequences.
• Identification of conserved domains and essential residues for channel function.
• Comparative analysis of Orai protein evolution across different lineages, from archaea to vertebrates.

Main Results:

• Lineage-specific duplication events in the Orai protein family were identified.
• A putative primordial Orai sequence was found in hyperthermophilic archaeons.
• Modern Orai proteins acquired new structural domains early in evolution, preceding vertebrate divergence, with conserved repeats in transmembrane segments crucial for function.

Conclusions:

• The evolutionary history of Orai proteins, including duplication events and domain acquisition, provides insights into the functional diversity of CRAC channels.
• Conserved structural features in Orai proteins are essential for their channel function.
• Understanding the evolutionary origins of Orai proteins offers a framework for future structural and functional studies.