The STIM-Orai Pathway: STIM-Orai Structures: Isolated and in Complex

Abstract

Considerable progress has been made elucidating the molecular mechanisms of calcium (Ca²⁺) sensing by stromal interaction molecules (STIMs) and the basis for Orai channel activity. This chapter focuses on the available high-resolution structural details of STIM and Orai proteins with respect to the regulation of store-operated Ca²⁺ entry (SOCE). Solution structures of the Ca²⁺-sensing domains of STIM1 and STIM2 are reviewed in detail, crystal structures of cytosolic coiled-coil STIM fragments are discussed, and an overview of the closed Drosophila melanogaster Orai hexameric structure is provided. Additionally, we highlight structures of human Orai1 N-terminal and C-terminal domains in complex with calmodulin and human STIM1, respectively. Ultimately, the accessible structural data are discussed in terms of potential mechanisms of action and cohesiveness with functional observations.

Keywords: Calmodulin; Orai1; Solution nuclear magnetic resonance spectroscopy; Store-operated calcium entry; Stromal interaction molecules; Structural mechanisms; X-ray crystallography.