Structure and function of endoplasmic reticulum STIM calcium sensors

Abstract

Store-operated calcium (Ca(2+)) entry (SOCE) is a vital Ca(2+) signaling pathway in nonexcitable as well as electrically excitable cells, regulating countless physiological and pathophysiological pathways. Stromal interaction molecules (STIMs) are the principal regulating molecules of SOCE, sensing changes in sarco-/endoplasmic reticulum (S/ER) luminal Ca(2+) levels and directly interacting with the Orai channel subunits to orchestrate the opening of Ca(2+) release-activated Ca(2+) (CRAC) channels. Recent atomic resolution structures on human STIM1 and STIM2 have illuminated critical mechanisms of STIM function in SOCE; further, the first high-resolution structure of the Drosophila melanogaster Orai channel has revealed vital data on the atomic composition of the CRAC channel pore and the assembly of individual Orai subunits. This chapter focuses on the mechanistic information garnered from these high-resolution structures and the supporting biophysical, biochemical, and live cell work that has enhanced our understanding of the relationship between STIM and Orai structural features and CRAC channel function.

Keywords: Calcium release-activated calcium; Nuclear magnetic resonance spectroscopy; Orai1; STIM1; STIM2; Store-operated calcium entry; Stromal interaction molecule; X-ray crystallography.