scholarly journals Structural Insights into Ca2+ Permeation through Orai Channels

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3062
Author(s):  
Yang Li ◽  
Xue Yang ◽  
Yuequan Shen
Keyword(s):  
Calcium Release ◽  
Structural Features ◽  
Structural Studies ◽  
Excitable Cells ◽  
Functional Studies ◽  
Gating Mechanism ◽  
Crac Channel ◽  
Open States ◽  
Structural Insights ◽  
Orai Channels

Orai channels belong to the calcium release-activated calcium (CRAC) channel family. Orai channels are responsible for the influx of extracellular Ca2+ that is triggered by Ca2+ depletion from the endoplasmic reticulum (ER); this function is essential for many types of non-excitable cells. Extensive structural and functional studies have advanced the knowledge of the molecular mechanism by which Orai channels are activated. However, the gating mechanism that allows Ca2+ permeation through Orai channels is less well explained. Here, we reviewed and summarized the existing structural studies of Orai channels. We detailed the structural features of Orai channels, described structural comparisons of their closed and open states, and finally proposed a “push–pull” model of Ca2+ permeation.

scholarly journals Regulation of Store-Operated Ca2+ Entry by SARAF

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1887
Author(s):  
Inbal Dagan ◽  
Raz Palty
Keyword(s):  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Cellular Biology ◽  
Excitable Cells ◽  
Major Pathway ◽  
Negative Feedback Mechanism ◽  
Crac Channels ◽  
Dependent Inactivation ◽  
Crac Channel ◽  
The One

Calcium (Ca2+) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca2+ signaling in cells.

scholarly journals Unravelling calcium-release channel gating: clues from a hot disease

2004 ◽  
Vol 380 (1) ◽  
pp. e1-e3 ◽  
Author(s):  
Tommie V. McCARTHY ◽  
John J. MACKRILL
Keyword(s):  
Calcium Release ◽  
Distinct Point ◽  
Ryanodine Receptors ◽  
Point Mutations ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Present Evidence ◽  
Gating Mechanism ◽  
Biochemical Journal ◽  
Interdomain Interactions

Ryanodine receptors (RyRs) are a family of intracellular channels that mediate Ca2+ release from the endoplasmic and sarcoplasmic reticulum. More than 50 distinct point mutations in one member of this family, RyR1, cause malignant hyperthermia, a potentially lethal pharmacogenetic disorder of skeletal muscle. These mutations are not randomly distributed throughout the primary structure of RyR1, but are grouped in three discrete clusters. In this issue of the Biochemical Journal, Kobayashi et al. present evidence that interdomain interactions between two of these mutation-enriched regions play a key role in the gating mechanism of RyR1.

scholarly journals Triadin Binding to the C-Terminal Luminal Loop of the Ryanodine Receptor is Important for Skeletal Muscle Excitation–Contraction Coupling

2007 ◽  
Vol 130 (4) ◽  
pp. 365-378 ◽  
Author(s):  
Sanjeewa A. Goonasekera ◽  
Nicole A. Beard ◽  
Linda Groom ◽  
Takashi Kimura ◽  
Alla D. Lyfenko ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Calcium Release ◽  
Striated Muscle ◽  
Single Channel ◽  
Triple Mutant ◽  
Double Mutation ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Functional Studies

Ca2+ release from intracellular stores is controlled by complex interactions between multiple proteins. Triadin is a transmembrane glycoprotein of the junctional sarcoplasmic reticulum of striated muscle that interacts with both calsequestrin and the type 1 ryanodine receptor (RyR1) to communicate changes in luminal Ca2+ to the release machinery. However, the potential impact of the triadin association with RyR1 in skeletal muscle excitation–contraction coupling remains elusive. Here we show that triadin binding to RyR1 is critically important for rapid Ca2+ release during excitation–contraction coupling. To assess the functional impact of the triadin-RyR1 interaction, we expressed RyR1 mutants in which one or more of three negatively charged residues (D4878, D4907, and E4908) in the terminal RyR1 intraluminal loop were mutated to alanines in RyR1-null (dyspedic) myotubes. Coimmunoprecipitation revealed that triadin, but not junctin, binding to RyR1 was abolished in the triple (D4878A/D4907A/E4908A) mutant and one of the double (D4907A/E4908A) mutants, partially reduced in the D4878A/D4907A double mutant, but not affected by either individual (D4878A, D4907A, E4908A) mutations or the D4878A/E4908A double mutation. Functional studies revealed that the rate of voltage- and ligand-gated SR Ca2+ release were reduced in proportion to the degree of interruption in triadin binding. Ryanodine binding, single channel recording, and calcium release experiments conducted on WT and triple mutant channels in the absence of triadin demonstrated that the luminal loop mutations do not directly alter RyR1 function. These findings demonstrate that junctin and triadin bind to different sites on RyR1 and that triadin plays an important role in ensuring rapid Ca2+ release during excitation–contraction coupling in skeletal muscle.

Active Fault Systems in the inner North West Apennines: an updated view

2021 ◽  
Author(s):  
Giancarlo Molli ◽  
Rick Bennett ◽  
Jacques Malavieille ◽  
Enrico Serpelloni ◽  
Fabrizio Storti ◽  
...  
Keyword(s):  
Active Fault ◽  
Central Italy ◽  
Structural Features ◽  
Structural Studies ◽  
Data Set ◽  
Structural Domains ◽  
North West ◽  
Fault Systems ◽  
Internal Fault ◽  
Fault Characterization

<p>As part of an ongoing project of mapping, structural studies and fault characterization we present an updated tectonic scheme and data set for the active fault systems that shaped the inner portion of the Apennines north of the Arno river. Geomorphology, stratigraphy of Plio-Quaternary sediments, GPS data, historical and instrumental seismicity have been reviewed and combined with structural studies to define the neotectonic history of the investigated region. Within the studied area, first-order physiographic and structural features allow to define different structural domains related to a set of ranges with a dominant NW-SE direction separated by intramontane or continental/marine morphotectonic depressions of the Lunigiana, Garfagnana, Lucca-Mt.Albano, La Spezia-Carrara and the off-shore Viareggio basin. The main boundary faults and internal fault segments of the different structural domains were described while the Plio-Quaternary sedimentary records has been used to constrain their long to short term deformation and rates, with the aim to improve current Italian catalogues - DISS (INGV) and Ithaca (ISPRA) - with some utilities for the seismic microzonation local projects. Moreover, our work aims to draw the attention of the scientific community to the seismotectonics of a region in which the seismic hazard is largely considered medium to low despite the occurrence, one century ago, of one of the most destructive earthquakes that have struck the Italian peninsula, the 1920 Fivizzano EQ, with an estimated Mw 6.5 similar to the main shock of the 2016 Central Italy seismic sequence.</p><p> </p>

scholarly journals A Dual Role for Saraf in Regulation of Calcium-Release Activated Calcium (CRAC) Channel Activity

2020 ◽  
Vol 118 (3) ◽  
pp. 406a
Author(s):  
Elia Zumot ◽  
Hadas Achildiev ◽  
Raz Palty
Keyword(s):  
Calcium Release ◽  
Dual Role ◽  
Channel Activity ◽  
Crac Channel

scholarly journals Structural insights into ADP-ribosylation of ubiquitin by Deltex family E3 ubiquitin ligases

2020 ◽  
Vol 6 (38) ◽  
pp. eabc0418
Author(s):  
Chatrin Chatrin ◽  
Mads Gabrielsen ◽  
Lori Buetow ◽  
Mark A. Nakasone ◽  
Syed F. Ahmed ◽  
...  
Keyword(s):  
Cross Talk ◽  
Posttranslational Modifications ◽  
Unknown Function ◽  
Carboxyl Terminus ◽  
Structural Studies ◽  
Future Studies ◽  
Adp Ribosylation ◽  
Carboxyl Terminal ◽  
Adp Ribosyltransferase ◽  
Structural Insights

Cellular cross-talk between ubiquitination and other posttranslational modifications contributes to the regulation of numerous processes. One example is ADP-ribosylation of the carboxyl terminus of ubiquitin by the E3 DTX3L/ADP-ribosyltransferase PARP9 heterodimer, but the mechanism remains elusive. Here, we show that independently of PARP9, the conserved carboxyl-terminal RING and DTC (Deltex carboxyl-terminal) domains of DTX3L and other human Deltex proteins (DTX1 to DTX4) catalyze ADP-ribosylation of ubiquitin’s Gly76. Structural studies reveal a hitherto unknown function of the DTC domain in binding NAD+. Deltex RING domain recruits E2 thioesterified with ubiquitin and juxtaposes it with NAD+ bound to the DTC domain to facilitate ADP-ribosylation of ubiquitin. This ubiquitin modification prevents its activation but is reversed by the linkage nonspecific deubiquitinases. Our study provides mechanistic insights into ADP-ribosylation of ubiquitin by Deltex E3s and will enable future studies directed at understanding the increasingly complex network of ubiquitin cross-talk.

scholarly journals Intra-locked G-quadruplex structures formed by irregular DNA G-rich motifs

2020 ◽  
Vol 48 (6) ◽  
pp. 3315-3327 ◽  
Author(s):  
Arijit Maity ◽  
Fernaldo Richtia Winnerdy ◽  
Weili Denyse Chang ◽  
Gang Chen ◽  
Anh Tuân Phan
Keyword(s):  
Human Genome ◽  
Dna Sequences ◽  
Structural Features ◽  
Nmr Structure ◽  
Solution Nmr ◽  
Structural Studies ◽  
High Propensity ◽  
G Quadruplex ◽  
High Prevalence

Abstract G-rich DNA sequences with tracts of three or more continuous guanines (G≥3) are known to have high propensity to adopt stable G-quadruplex (G4) structures. Bioinformatic analyses suggest high prevalence of G-rich sequences with short G-tracts (G≤2) in the human genome. However, due to limited structural studies, the folding principles of such sequences remain largely unexplored and hence poorly understood. Here, we present the solution NMR structure of a sequence named AT26 consisting of irregularly spaced G2 tracts and two isolated single guanines. The structure is a four-layered G4 featuring two bi-layered blocks, locked between themselves in an unprecedented fashion making it a stable scaffold. In addition to edgewise and propeller-type loops, AT26 also harbors two V-shaped loops: a 2-nt V-shaped loop spanning two G-tetrad layers and a 0-nt V-shaped loop spanning three G-tetrad layers, which are named as VS- and VR-loop respectively, based on their distinct structural features. The intra-lock motif can be a basis for extending the G-tetrad core and a very stable intra-locked G4 can be formed by a sequence with G-tracts of various lengths including several G2 tracts. Findings from this study will aid in understanding the folding of G4 topologies from sequences containing irregularly spaced multiple short G-tracts.

scholarly journals Structural insights into heme binding to IL-36α proinflammatory cytokine

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Amelie Wißbrock ◽  
Nishit B. Goradia ◽  
Amit Kumar ◽  
Ajay Abisheck Paul George ◽  
Toni Kühl ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Investigation ◽  
Inflammatory Responses ◽  
Structural Features ◽  
Solution Nmr ◽  
Heme Binding ◽  
Structural Framework ◽  
Spectroscopic Analyses ◽  
Structural Insights ◽  
Fibroblast Like Synoviocytes

AbstractCytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.

scholarly journals PACRG and FAP20 form the inner junction of axonemal doublet microtubules and regulate ciliary motility

2019 ◽  
Vol 30 (15) ◽  
pp. 1805-1816 ◽  
Author(s):  
Erin E. Dymek ◽  
Jianfeng Lin ◽  
Gang Fu ◽  
Mary E. Porter ◽  
Daniela Nicastro ◽  
...  
Keyword(s):  
Cell Motility ◽  
Electron Tomography ◽  
Structural Studies ◽  
Ciliary Beating ◽  
Ciliary Motility ◽  
Functional Studies ◽  
Cryo Electron Tomography ◽  
Motile Cilia

We previously demonstrated that PACRG plays a role in regulating dynein-driven microtubule sliding in motile cilia. To expand our understanding of the role of PACRG in ciliary assembly and motility, we used a combination of functional and structural studies, including newly identified Chlamydomonas pacrg mutants. Using cryo-electron tomography we show that PACRG and FAP20 form the inner junction between the A- and B-tubule along the length of all nine ciliary doublet microtubules. The lack of PACRG and FAP20 also results in reduced assembly of inner-arm dynein IDA b and the beak-MIP structures. In addition, our functional studies reveal that loss of PACRG and/or FAP20 causes severe cell motility defects and reduced in vitro microtubule sliding velocities. Interestingly, the addition of exogenous PACRG and/or FAP20 protein to isolated mutant axonemes restores microtubule sliding velocities, but not ciliary beating. Taken together, these studies show that PACRG and FAP20 comprise the inner junction bridge that serves as a hub for both directly modulating dynein-driven microtubule sliding, as well as for the assembly of additional ciliary components that play essential roles in generating coordinated ciliary beating.

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