Faculty, Staff and Student Publications

Language

English

Publication Date

4-13-2026

Journal

Nature Communications

DOI

10.1038/s41467-026-71769-2

PMID

41974720

PMCID

PMC13077005

PubMedCentral® Posted Date

4-13-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Store-operated Ca2+ release-activated Ca2+ (CRAC) channels, composed of STIM and ORAI, are essential for immune and developmental processes, and their dysregulation underlies channelopathies such as Stormorken syndrome. Here, we report the engineering of genetically encoded CRAC channel inhibitory binders (CRABs) derived from the ORAI C-terminal tail. Guided by deep mutational scanning, we optimize a membrane-anchored CRAB variant that potently inhibits Ca2+ influx and NFAT signaling, and rescues thrombocytopenia-like phenotypes in a zebrafish model of Stormorken syndrome. To enable tunable inhibition, we further design oligomeric, optogenetic (Opto-CRAB), and chemogenetic (Chemo-CRAB) variants, providing graded and real-time control of CRAC activity. Chemo-CRAB further suppresses Ca2+ signaling downstream of RTKs, GPCRs, and CAR-T cell activation, establishing broad applicability across physiological and synthetic contexts. Together, these programmable peptide-based inhibitors provide a versatile platform to dissect SOCE dynamics and hold promise as a therapeutic strategy against autoimmune, inflammatory, and neoplastic disorders driven by CRAC channel hyperactivity.

Keywords

Animals, Zebrafish, Humans, Calcium Release Activated Calcium Channels, Calcium Signaling, Calcium, ORAI1 Protein, HEK293 Cells, Calcium Channel Blockers, Optogenetics, Protein Engineering, Disease Models, Animal, Peptides, Stromal Interaction Molecule 1, Optogenetics, Calcium channels, Zebrafish, Peptides

Published Open-Access

yes

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