The roles of transmembrane family proteins in the regulation of store-operated Ca2+ entry

Abstract

Store-operated Ca²⁺ entry (SOCE) is a major pathway for calcium signaling, which regulates almost every biological process, involving cell proliferation, differentiation, movement and death. Stromal interaction molecule (STIM) and ORAI calcium release-activated calcium modulator (ORAI) are the two major proteins involved in SOCE. With the deepening of studies, more and more proteins are found to be able to regulate SOCE, among which the transmembrane (TMEM) family proteins are worth paying more attention. In addition, the ORAI proteins belong to the TMEM family themselves. As the name suggests, TMEM family is a type of proteins that spans biological membranes including plasma membrane and membrane of organelles. TMEM proteins are in a large family with more than 300 proteins that have been already identified, while the functional knowledge about the proteins is preliminary. In this review, we mainly summarized the TMEM proteins that are involved in SOCE, to better describe a picture of the interaction between STIM and ORAI proteins during SOCE and its downstream signaling pathways, as well as to provide an idea for the study of the TMEM family proteins.

Keywords: CRAC; Ca2+ release-activated calcium channel; Calcium; ER–PM junction; Ion channel gating; Membrane protein; ORAI1; Protein–protein interaction; SARAF; STIM1; STING; Store-operated channel.

Fig. 1

Interaction between TMEM family proteins and STIM1/ORAI1. STIM1 multimerizes and translocates from ER to the ER–PM junctions after store depletion, activating ORAI1 channels and allowing Ca²⁺ influx from the extracellular environment. TMEM family proteins interact with different domains of STIM1 and/or ORAI1, dynamically regulate SOCE