Dataset Information

Structural and functional mechanisms of CRAC channel regulation.

ABSTRACT: In many animal cells, stimulation of cell surface receptors coupled to G proteins or tyrosine kinases mobilizes Ca(2+) influx through store-operated Ca(2+)-release-activated Ca(2+) (CRAC) channels. The ensuing Ca(2+) entry regulates a wide variety of effector cell responses including transcription, motility, and proliferation. The physiological importance of CRAC channels for human health is underscored by studies indicating that mutations in CRAC channel genes produce a spectrum of devastating diseases including chronic inflammation, muscle weakness, and a severe combined immunodeficiency syndrome. Moreover, from a basic science perspective, CRAC channels exhibit a unique biophysical fingerprint characterized by exquisite Ca(2+) selectivity, store-operated gating, and distinct pore properties and therefore serve as fascinating model ion channels for understanding the biophysical mechanisms of Ca(2+) selectivity and channel opening. Studies in the last two decades have revealed the cellular and molecular choreography of the CRAC channel activation process, and it is now established that opening of CRAC channels is governed through direct interactions between the pore-forming Orai proteins and the endoplasmic reticulum Ca(2+) sensors STIM1 and STIM2. In this review, we summarize the functional and structural mechanisms of CRAC channel regulation, focusing on recent advances in our understanding of the conformational and structural dynamics of CRAC channel gating.

SUBMITTER: Shim AH

PROVIDER: S-EPMC4459506 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural and functional mechanisms of CRAC channel regulation.

Shim Ann Hye-Ryong AH Tirado-Lee Leidamarie L Prakriya Murali M

Journal of molecular biology 20141002 1

In many animal cells, stimulation of cell surface receptors coupled to G proteins or tyrosine kinases mobilizes Ca(2+) influx through store-operated Ca(2+)-release-activated Ca(2+) (CRAC) channels. The ensuing Ca(2+) entry regulates a wide variety of effector cell responses including transcription, motility, and proliferation. The physiological importance of CRAC channels for human health is underscored by studies indicating that mutations in CRAC channel genes produce a spectrum of devastating ...[more]

PMID: 25284754

Similar Datasets

Project description:Store-operated Ca2+ entry occurs through the binding of the endoplasmic reticulum (ER) Ca2+ sensor STIM1 to Orai1, the pore-forming subunit of the Ca2+ release-activated Ca2+ (CRAC) channel. Although the essential steps leading to channel opening have been described, fundamental questions remain, including the functional stoichiometry of the CRAC channel. The crystal structure of Drosophila Orai indicates a hexameric stoichiometry, while studies of linked Orai1 concatemers and single-molecule photobleaching suggest that channels assemble as tetramers. We assessed CRAC channel stoichiometry by expressing hexameric concatemers of human Orai1 and comparing in detail their ionic currents to those of native CRAC channels and channels generated from monomeric Orai1 constructs. Cell surface biotinylation results indicated that Orai1 channels in the plasma membrane were assembled from intact hexameric polypeptides and not from truncated protein products. In addition, the L273D mutation depressed channel activity equally regardless of which Orai1 subunit in the concatemer carried the mutation. Thus, functional channels were generated from intact Orai1 hexamers in which all subunits contributed equally. These hexameric Orai1 channels displayed the biophysical fingerprint of native CRAC channels, including the distinguishing characteristics of gating (store-dependent activation, Ca2+-dependent inactivation, open probability), permeation (ion selectivity, affinity for Ca2+ block, La3+ sensitivity, unitary current magnitude), and pharmacology (enhancement and inhibition by 2-aminoethoxydiphenyl borate). Because permeation characteristics depend strongly on pore geometry, it is unlikely that hexameric and tetrameric pores would display identical Ca2+ affinity, ion selectivity, and unitary current magnitude. Thus, based on the highly similar pore properties of the hexameric Orai1 concatemer and native CRAC channels, we conclude that the CRAC channel functions as a hexamer of Orai1 subunits.

Dataset Information

Structural and functional mechanisms of CRAC channel regulation.

Publications

Structural and functional mechanisms of CRAC channel regulation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets