PDBsum entry 6o2v

Signaling protein

PDB id: 6o2v

Contents

Protein chains

135 a.a.

Ligands

FMT

GOL

Waters ×320

References listed in PDB file

Key reference

• Title: Saraf luminal domain structure reveals a novel domain-Swapped β-Sandwich fold important for soce modulation.
• Authors: C.R.Kimberlin, A.Meshcheriakova, R.Palty, A.Raveh, I.Karbat, E.Reuveny, D.L.Minor.
• Ref.: J Mol Biol, 2019, 431, 2869-2883. [DOI no: 10.1016/j.jmb.2019.05.008]
• PubMed id: 31082439

Abstract

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. SARAF, 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 SARAF luminal domain, SARAF_L. This domain forms a novel 10-stranded β-sandwich fold that includes a set of three conserved disulfide bonds, denoted the "SARAF-fold." The structure reveals a domain-swapped dimer in which the last two β-strands (β9 and β10) are exchanged forming a region denoted the "SARAF luminal switch" that is essential for dimerization. Sequence comparisons reveal that the SARAF-fold is highly conserved in vertebrates and in a variety of pathologic fungi. Förster resonance energy transfer experiments using full-length SARAF validate the formation of the domain-swapped dimer in cells and demonstrate that dimerization is reversible. A designed variant lacking the SARAF luminal switch shows that the domain swapping is essential to function and indicates that the SARAF dimer accelerates SOCE inactivation.