ArticleThe Journal of biological chemistry2009
Increased hydrophobicity at the N terminus/membrane interface impairs gating of the severe combined immunodeficiency-related ORAI1 mutant.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 78 citations in OpenAlex.
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- Orai1 acts as a novel CaExperimental & molecular medicine · 2026Article
- Store-Operated Calcium Channels in the Nervous System.Annual review of physiology · 2025Review
- Side-by-side comparison of published small molecule inhibitors against thapsigargin-induced store-operated Ca2+ entry in HEK293 cells.PloS one · 2024Article
- The Role of Lipids in CRAC Channel Function.Biomolecules · 2022Review
- Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions.Cells · 2022Review
- Structural Insights into CaCells · 2021Review
- Novel ORAI1 Mutation Disrupts Channel Trafficking Resulting in Combined Immunodeficiency.Journal of clinical immunology · 2021Article
- The Orai Pore Opening Mechanism.International journal of molecular sciences · 2021Review
- Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner.Frontiers in cell and developmental biology · 2021Article
- Molecular basis of allosteric Orai1 channel activation by STIM1.The Journal of physiology · 2020Review
- The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate.The Journal of general physiology · 2020Article
- Critical parameters maintaining authentic CRAC channel hallmarks.European biophysics journal : EBJ · 2019Review
- Article
- Communication between N terminus and loop2 tunes Orai activation.The Journal of biological chemistry · 2018Article
- Transmembrane helix connectivity in Orai1 controls two gates for calcium-dependent transcription.Science signaling · 2017Article
- The STIM-Orai Pathway: Orai, the Pore-Forming Subunit of the CRAC Channel.Advances in experimental medicine and biology · 2017Review
- Molecular mechanisms of STIM/Orai communication.American journal of physiology. Cell physiology · 2016Review
- The inactivation domain of STIM1 is functionally coupled with the Orai1 pore to enable Ca2+-dependent inactivation.The Journal of general physiology · 2016Article
- Cholesterol modulates Orai1 channel function.Science signaling · 2016Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
Patients with severe combined immune deficiency (SCID) suffer from defective T-cell Ca2+ signaling. A loss of Ca2+ entry has been linked at the molecular level to single missense mutation R91W in the store-operated Ca2+ channel ORAI1. However, the mechanistic impact of this mutation on ORAI1 function remains unclear. Confocal Förster resonance energy transfer microscopy revealed that dynamic store-operated coupling of STIM1 to ORAI1 R91W was largely sustained similar to wild-type ORAI1. Characterization of various point mutants at position 91 by whole cell patch clamp recordings displayed that neutral or even negatively charged amino acids did not abolish ORAI1 function. However, substitution by hydrophobic leucine, valine, or phenylalanine resulted in non-functional ORAI1 channels, despite preserved STIM1 coupling. Besides conformational constraints at the N terminus/membrane interface predicted for the hydrophobic mutants, additional key factor(s) were suggested to determine ORAI1 functionality. Calculation of the probability for the 1st transmembrane domain and its hydrophobicity revealed a substantial increase for all hydrophobic substitutions that lead to non-functional ORAI1 R91X mutants in contrast to those with hydrophilic residues. Hence, increased hydrophobicity might lead to disrupted permeation/gating, as an ORAI1 channel with increased pore size and R91W mutation failed to recover activity. In conclusion, the increase in hydrophobicity at the N terminus/membrane interface represents the major cause for yielding non-functional ORAI1 channels.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.