TMEM66 (Transmembrane protein 66, also known as SOCE-associated regulatory factor, SARAF) is a regulatory protein of cellular Ca²⁺ homeostasis, encoded by the TMEM66 gene. TMEM66 is an ER resident protein, which responds to cytosolic Ca²⁺ elevation after ER Ca²⁺ refilling.

TMEM66 is highly conserved in vertebrates. In mammals it is ubiquitously expressed with high transcript levels in the immune and neuronal tissues. The TMEM66 structure contains validated signal peptide and a putative single membrane spanning domain, a serine-proline rich domain and arginine rich regions followed by a cluster of basic residues at its C-terminal tail¹.

Store-operated Ca²⁺ entry (SOCE) is an important Ca²⁺ influx pathway across plasma membranes in many non-excitable cells. In this pathway, intracellular Ca²⁺ release through IP₃ receptors stimulated by a variety of agonists, results in reduction of Ca²⁺ concentration in the lumen of the endoplasmic or sarcoplasmic reticulum. SARAF negatively regulates store operated calcium entry into cells and protects cells from calcium overfilling^1,2.

STIM, Ca²⁺ sensor, and Orai, the channel pore forming subunit proteins have been identified as the essential components enabling the reconstitution of Ca²⁺ release-activated Ca²⁺ channels that mediate SOCE. Knock-out of Orai1 or STIM1 in mice and mutations evoke SOCE in lymphocytes and other cells^2,3.

Findings show that dysregulation of Ca²⁺ homeostasis is associated with a plethora of pathological conditions including neurodegenerative diseases, skeletal, muscular and cardiovascular disorders². Inherited defects in SOCE due to mutations in genes of the Ca²⁺ release-activated Ca²⁺ (CRAC) channel complex causes patients to suffer from a severe form of immunodeficiency that is due to defects in the function of T cells, NK cells and potentially other immune cells³_.