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Engineering of genetically encoded programmable calcium channel inhibitory binders
Xiaoxuan Liu1, Sher Ali1, Tien-Hung Lan1
1Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
Nature Communications
|April 13, 2026
Summary
Researchers engineered CRAC channel inhibitory binders (CRABs) to control calcium (Ca2+) signaling. These CRABs show therapeutic potential for channelopathies and autoimmune disorders by precisely modulating CRAC channel activity.
Area of Science:
- Molecular Biology
- Immunology
- Genetics
- Biochemistry
Background:
- Store-operated Ca2+ release-activated Ca2+ (CRAC) channels, formed by STIM and ORAI proteins, are crucial for immune responses and development.
- Dysregulation of CRAC channels leads to channelopathies, including Stormorken syndrome, highlighting the need for targeted modulation.
- Existing methods for controlling CRAC channel activity are limited in precision and real-time tunability.
Purpose of the Study:
- To engineer novel, genetically encoded inhibitors of CRAC channels.
- To develop tunable CRAC channel inhibitors for precise control of calcium signaling.
- To explore the therapeutic potential of these inhibitors in disease models.
Main Methods:
- Deep mutational scanning was employed to optimize CRAC channel inhibitory binders (CRABs).
- Engineered membrane-anchored CRAB variants were tested for their ability to inhibit Ca2+ influx and NFAT signaling.
- Oligomeric, optogenetic (Opto-CRAB), and chemogenetic (Chemo-CRAB) variants were designed for tunable and real-time CRAC activity control.
- A zebrafish model of Stormorken syndrome was used to assess the in vivo efficacy of CRABs.
Main Results:
- A potent, membrane-anchored CRAB variant was optimized, effectively inhibiting Ca2+ influx and NFAT signaling.
- CRABs successfully rescued thrombocytopenia-like phenotypes in a zebrafish model of Stormorken syndrome.
- Opto-CRAB and Chemo-CRAB variants provided graded and real-time control over CRAC channel activity.
- Chemo-CRAB demonstrated broad applicability by suppressing Ca2+ signaling downstream of various receptors and in CAR-T cell activation.
Conclusions:
- Programmable peptide-based inhibitors (CRABs) offer a versatile platform for dissecting store-operated calcium entry (SOCE) dynamics.
- Engineered CRAB variants provide precise, tunable control over CRAC channel activity in diverse biological contexts.
- These CRABs hold significant promise as a therapeutic strategy for autoimmune, inflammatory, and neoplastic disorders associated with CRAC channel hyperactivity.
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