ArticleThe Journal of biological chemistry2012
Crystal structure of calmodulin binding domain of orai1 in complex with Ca2+ calmodulin displays a unique binding mode.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 63 citations in OpenAlex.
- Evolutionarily conserved hydrophobicity and sterics in TM3/TM4 balance Orai1 pore opening.Protein science : a publication of the Protein Society · 2026Article
- Store-operated calcium entry-based targets for novel cancer therapeutic development.The Journal of pharmacology and experimental therapeutics · 2025Review
- Calmodulin binding is required for calcium mediated TRPA1 desensitization.Nature communications · 2025Article
- Oligomerization Function of the Native Exon 5 Sequence of Ameloblastin Fused with Calmodulin.ACS omega · 2025Article
- Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation.International journal of molecular sciences · 2023Review
- Orai1 is an Entotic CaAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Similarities and Differences between the Orai1 Variants: Orai1α and Orai1β.International journal of molecular sciences · 2022Review
- Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions.Cells · 2022Review
- STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases.Frontiers in aging · 2022Review
- Differential Expression of Genes Regulating Store-operated Calcium Entry in Conjunction With Mitochondrial Dynamics as Potential Biomarkers for Cancer: A Single-Cell RNA Analysis.Frontiers in genetics · 2022Article
- Regulation of Store-Operated CaCells · 2021Review
- Structure and Function of Ion Channels Regulating Sperm Motility-An Overview.International journal of molecular sciences · 2021Review
- More Than Just Simple Interaction between STIM and Orai Proteins: CRAC Channel Function Enabled by a Network of Interactions with Regulatory Proteins.International journal of molecular sciences · 2021Review
- The Penta-EF-Hand ALG-2 Protein Interacts with the Cytosolic Domain of the SOCE Regulator SARAF and Interferes with Ubiquitination.International journal of molecular sciences · 2020Article
- Store-Operated Calcium Channels: From Function to Structure and Back Again.Cold Spring Harbor perspectives in biology · 2020Review
- Contribution of Coiled-Coil Assembly to CaJournal of the American Society of Nephrology : JASN · 2019Article
- A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction.Nature communications · 2019Article
- Towards Understanding Plant Calcium Signaling through Calmodulin-Like Proteins: A Biochemical and Structural Perspective.International journal of molecular sciences · 2018Review
- Calmodulin dissociates the STIM1-Orai1 complex and STIM1 oligomers.Nature communications · 2017Article
- Synergy of cAMP and calcium signaling pathways in CFTR regulation.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Orai1 is a plasma membrane protein that in its tetrameric form is responsible for calcium influx from the extracellular environment into the cytosol in response to interaction with the Ca(2+)-depletion sensor STIM1. This is followed by a fast Ca(2+)·calmodulin (CaM)-dependent inhibition, resulting from CaM binding to an Orai1 region called the calmodulin binding domain (CMBD). The interaction between Orai1 and CaM at the atomic level remains unknown. Here, we report the crystal structure of a CaM·Orai1-CMBD complex showing one CMBD bound to the C-terminal lobe of CaM, differing from other CaM-target protein complexes, in which both N- and C-terminal lobes of CaM (CaM-N and CaM-C) are involved in target binding. Orai1-CMBD binds CaM-C mainly through hydrophobic interactions, primarily involving residue Trp(76) of Orai1-CMBD, which interacts with the hydrophobic pocket of CaM-C. However, NMR data, isothermal titration calorimetry data, and pulldown assays indicated that CaM-N and CaM-C both can bind Orai1-CMBD, with CaM-N having ∼4 times weaker affinity than CaM-C. Pulldown assays of a Orai1-CMBD(W76E) mutant, gel filtration chromatography data, and NOE signals indicated that CaM-N and CaM-C can each bind one Orai1-CMBD. Thus our studies support an unusual, extended 1:2 binding mode of CaM to Orai1-CMBDs, and quantify the affinity of Orai1 for CaM. We propose a two-step mechanism for CaM-dependent Orai1 inactivation initiated by binding of the C-lobe of CaM to the CMBD of one Orai1 followed by the binding of the N-lobe of CaM to the CMBD of a neighboring Orai1.
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