UC San Diego

We investigated the evolutionary origins of the Ca²⁺ Release-Activated Ca²⁺ (CRAC) Orai channel proteins of animals and the ubiquitous Cation Diffusion Facilitator (CDF) carrier proteins. CDF antiporters derived from a primordial 2 transmembrane spanner (TMS) hairpin structure by intragenic triplication to yield 6 TMS proteins. Surprisingly, members of the CDF family proved to be homologous to members of the 4 TMS Orai channel proteins. We provide evidence that CRAC channels derived from CDF carriers by loss of the first two TMSs of the latter. Thus, TMSs 3-6 in CDF carriers are homologous to TMSs 1-4 in CRAC channels. The former probably gave rise to the latter. This is an unusual example of how a functionally and structurally more complex protein may have predated a simpler one. CRAC channels were thought to be derived exclusively from animals but we have identified new Orai channel proteins which include the choanoflagellate. Interestingly, a Stim homologue was identified in the choanoflagellate but not in green algae. Domain and motif analysis reveals several conserved regions between Orai proteins that are likely to be of functional significance