A Deep Dive into the N-Terminus of STIM Proteins: Structure-Function Analysis and Evolutionary Significance of the Functional Domains

Biomolecules. 2024 Sep 24;14(10):1200. doi: 10.3390/biom14101200.

Abstract

Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca2+ levels ([Ca2+]i) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai proteins play important roles in maintaining [Ca2+]i through store-operated Ca2+ entry (SOCE), with STIM being the primary regulatory protein that governs the function of Orai channels. STIM1 and STIM2 are single-pass ER-transmembrane proteins with their N- and C-termini located in the ER lumen and cytoplasm, respectively. The N-terminal EF-SAM domain of STIMs senses [Ca2+]ER changes, while the C-terminus mediates clustering in ER-PM junctions and gating of Orai1. ER-Ca2+ store depletion triggers activation of the STIM proteins, which involves their multimerization and clustering in ER-PM junctions, where they recruit and activate Orai1 channels. In this review, we will discuss the structure, organization, and function of EF-hand motifs and the SAM domain of STIM proteins in relation to those of other eukaryotic proteins.

Keywords: EF-hand; SAM; SOCE; STIM1; STIM2; calcium signaling.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / metabolism
  • Evolution, Molecular
  • Humans
  • ORAI1 Protein / chemistry
  • ORAI1 Protein / genetics
  • ORAI1 Protein / metabolism
  • Protein Domains*
  • Stromal Interaction Molecule 1 / chemistry
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism
  • Stromal Interaction Molecules / genetics
  • Stromal Interaction Molecules / metabolism
  • Structure-Activity Relationship

Substances

  • Calcium
  • Stromal Interaction Molecule 1
  • ORAI1 Protein
  • Stromal Interaction Molecules

Grants and funding

Funding for this work was provided by NIDCR-DIR, NIH (Z01-DE00438-35) for I.S.A.