Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating

Proceedings of the National Academy of Sciences of the United States of America
Priscilla S-W YeungMurali Prakriya

Abstract

Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1-4 whose perturbation activates Orai1 channels independently of STIM1. Cysteine accessibility analysis and molecular-dynamics simulations indicated that constitutive activation of the most robust variant, H134S, arises from a pore conformational change that opens a hydrophobic gate to augment pore hydration, similar to gating evoked by STIM1. Mutational analysis of this locus suggests that H134 acts as steric brake to stabilize the closed state of the channel. In addition, atomic packing analysis revealed distinct functional contacts between the TM1 pore helix and the surrounding TM2/3 helices, including one set mediated by a cluster of interdigitating hydrophobic residues and another by alternative ridges of polar and hydrophobic residues. Perturbing...Continue Reading

References

Jun 11, 1993·Science·M BlaberB W Matthews
Dec 1, 1996·Journal of Molecular Graphics·O S SmartM S Sansom
Jan 20, 1999·Proceedings of the National Academy of Sciences of the United States of America·S C LovellD C Richardson
Sep 2, 2004·Biophysical Journal·Aaron K Chamberlain, James U Bowie
Aug 19, 2007·The Journal of Biological Chemistry·Zhengzheng LiTao Xu
May 24, 2008·The Journal of Biological Chemistry·Rainer SchindlChristoph Romanin
Oct 4, 2008·The Journal of Physiology·Laura Navarro-BorellyMurali Prakriya
Feb 3, 2009·Nature Cell Biology·Joseph P YuanShmuel Muallem
Aug 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Franklin M MullinsRichard S Lewis
Dec 19, 2009·Proceedings of the National Academy of Sciences of the United States of America·Beth A McNallyMurali Prakriya
Dec 29, 2009·Nature Structural & Molecular Biology·Yubin ZhouPatrick G Hogan
Jan 30, 2010·Pflügers Archiv : European journal of physiology·Stefan Feske
Dec 1, 2010·The Journal of General Physiology·Annette LisReinhold Penner
Jan 27, 2012·Nature·Beth A McNallyMurali Prakriya
Nov 28, 2012·Science·Xiaowei HouStephen B Long
Aug 15, 2013·The Journal of Biological Chemistry·Isabella DerlerChristoph Romanin
Oct 9, 2013·Proceedings of the National Academy of Sciences of the United States of America·Hao DongMichael L Klein
Feb 26, 2014·The Journal of General Physiology·Megumi Yamashita, Murali Prakriya
Mar 5, 2014·Proceedings of the National Academy of Sciences of the United States of America·Vasyl NesinLeonidas Tsiokas
Jul 30, 2014·The Journal of Physical Chemistry. B·Hao DongGiacomo Fiorin
Oct 10, 2014·Nature Communications·Aparna GudlurPatrick G Hogan
Jun 4, 2015·PloS One·Leidamarie Tirado-LeeMurali Prakriya
Jul 4, 2015·Cell Research·Raz PaltyEhud Y Isacoff
Sep 25, 2015·Physiological Reviews·Murali Prakriya, Richard S Lewis
Oct 16, 2015·Annals of the New York Academy of Sciences·Rodrigo S Lacruz, Stefan Feske
Aug 28, 2016·Cell·Jean-Pierre Changeux, Arthur Christopoulos
Dec 9, 2016·Nature Communications·Yandong ZhouDonald L Gill
Jan 7, 2017·Human Mutation·Johann BöhmJocelyn Laporte
Jan 22, 2017·Cell Calcium·Priscilla S-W YeungMurali Prakriya
Feb 22, 2017·Nature Communications·Megumi YamashitaMurali Prakriya
Jun 1, 2017·Cell Reports·Raz PaltyEhud Y Isacoff
Dec 15, 2017·The Journal of Biological Chemistry·Marc FahrnerIsabella Derler
Dec 15, 2017·The Journal of Biological Chemistry·Isabella DerlerChristoph Romanin

❮ Previous
Next ❯

Citations

Aug 31, 2018·ELife·Xiaowei HouStephen Barstow Long
Apr 6, 2019·The Journal of Physiology·Priscilla See-Wai YeungMurali Prakriya
Dec 10, 2019·The Journal of General Physiology·Megumi YamashitaMurali Prakriya
Sep 16, 2018·The Journal of General Physiology·Priscilla See-Wai Yeung, Murali Prakriya
Oct 2, 2019·Cold Spring Harbor Perspectives in Biology·Richard S Lewis
Mar 25, 2019·European Biophysics Journal : EBJ·Adéla KrizovaIsabella Derler
Aug 31, 2019·PLoS Biology·Yandong ZhouDonald L Gill
Oct 31, 2020·ELife·Priscilla S-W YeungMurali Prakriya
Dec 15, 2020·Cell Calcium·Daniel BonhenryRainer Schindl
Dec 29, 2020·The Journal of Biological Chemistry·Adéla TiffnerIsabella Derler
Jan 8, 2021·Current Opinion in Physiology·Matthias SallingerIrene Frischauf
Jan 13, 2021·International Journal of Molecular Sciences·Adéla TiffnerIsabella Derler
Jan 30, 2021·Frontiers in Cell and Developmental Biology·Aurora Gil-HernándezAlejandro Silva-Palacios
Feb 14, 2021·Cell Calcium·Murali PrakriyaMegumi Yamashita
Jan 29, 2021·Scientific Reports·Rawad HodeifyKhaled Machaca
Mar 4, 2021·Cell Research·Sarah A KazzazDonald L Gill
Mar 2, 2021·Frontiers in Cell and Developmental Biology·Adéla TiffnerIsabella Derler
Aug 8, 2021·International Journal of Molecular Sciences·Adéla Tiffner, Isabella Derler
Nov 20, 2021·Frontiers in Molecular Biosciences·Xiaoqian ZhangChen Song

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.