SARAF Luminal Domain Structure Reveals a Novel Domain-Swapped β-Sandwich Fold Important for SOCE Modulation.

Store-Operated Calcium Entry (SOCE) plays key roles in cell proliferation, muscle contraction, immune responses, and memory formation. The coordinated interactions of a number of proteins from the plasma and endoplasmic reticulum membranes control SOCE to replenish internal Ca²⁺ stores and generate intracellular Ca²⁺ signals. an endoplasmic reticulum resident component of the SOCE pathway having no homology to any characterized protein, serves as an important brake on SOCE. Here, we describe the X-ray crystal structure of the luminal domain, This domain forms a novel 10-stranded β-sandwich fold that includes a set of three conserved disulfide bonds, denoted the The structure reveals a domain-swapped dimer in which the last two β-strands (β9 and β10) are exchanged forming a region denoted the luminal switch" that is essential for dimerization. Sequence comparisons reveal that the is highly conserved in vertebrates and in a variety of pathologic fungi. Förster resonance energy transfer experiments using full-length duanyu1800F validate the formation of the domain-swapped dimer in cells and demonstrate that dimerization is reversible. A designed variant lacking the duanyu1800F luminal switch shows that the domain swapping is essential to function and indicates that the duanyu1800F dimer accelerates SOCE inactivation.

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