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The STIM1: Orai Interaction

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Calcium Entry Pathways in Non-excitable Cells

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 898))

Abstract

Ca2+ influx via store-operated Ca2+ release activated Ca2+ (CRAC) channels represents a main signalling pathway for a variety of cell functions, including T-cell activation as well as mast-cell degranulation. Depletion of [Ca2+]ER results in activation of Ca2+ channels within the plasmamembrane that mediate sustained Ca2+ influx which is required for refilling Ca2+ stores and down-stream Ca2+ signalling. The CRAC channel is the best characterized store-operated channel (SOC) with well-defined electrophysiological properties. In recent years, the molecular components of the CRAC channel have been defined. The ER – located Ca2+-sensor, STIM1 and the Ca2+-selective ion pore, Orai1 in the membrane are sufficient to fully reconstitute CRAC currents. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca2+]ER and activates the CRAC channel upon store depletion by direct binding to Orai1 in the plasmamembrane. The identification of STIM1 and Orai1 and recently the structural resolution of both proteins by X-ray crystallography and nuclear magnetic resonance substantiated many findings from structure-function studies which has substantially improved the understanding of CRAC channel activation. Within this review, we summarize the functional and structural mechanisms of CRAC channel regulation, present a detailed overview of the STIM1/Orai1 signalling pathway where we focus on the critical domains mediating interactions and on the ion permeation pathway. We portray a mechanistic view of the steps in the dynamics of CRAC channel signalling ranging from STIM1 oligomerization over STIM1-Orai1 coupling to CRAC channel activation and permeation.

Author contributed equally with all other contributors.

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Abbreviations

2-APB:

2-Aminoethoxydiphenyl borate

Å:

Angstrom

Ca2+ :

Calcium

CAD:

CRAC activating domain

CC:

Coiled coil

CCb9:

Coiled coil containing region b9

CCE:

Capacitative calcium entry

CDI:

Calcium dependent inactivation

CFP:

Cyan fluorescent protein

CMD:

CRAC modulatory domain

CRAC:

Calcium release activated calcium

Cs+ :

Caesium

dOrai:

Drosophila melanogaster Orai

ER:

Endoplasmic reticulum

Et al:

Et alii

ETON:

Extended transmembrane Orai1 N-terminal region

FRET:

Förster resonance energy transfer

IH:

Inhibitory helix

IP3 :

Inositol(1,4,5)triphosphate

K-rich:

Lysine rich

Na+ :

Sodium

NMR:

Nuclear magnetic resonance

OASF:

Orai activating small fragment

PLC:

Phospholipase C

PM:

Plasmamembrane

RNAi:

Interference ribonucleic acid

SAM:

Sterile alpha motif

SCID:

Severe combined immunodeficiency

SERCA:

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SHD:

STIM1 homomerization domain

SOAP:

STIM/Orai association pocket

SOAR:

STIM/Orai activating region

SOCE:

Store operated calcium entry

STIM:

Stromal interaction molecule

TG:

Thapsigargin

TM:

Transmembrane

TRP:

Transient receptor potential

YFP:

Yellow fluorescent protein

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Acknowledgments

This work was supported by the Austrian Science Fund (FWF projects P25172 and P27263 to C.R. and V 286-B21 to I.F.).

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    Authors and Affiliations

    1. Institute of Biophysics, University of Linz, Linz, Austria

      Irene Frischauf, Marc Fahrner & Christoph Romanin

    2. Department of Physiology, University of Extremadura, Cáceres, Spain

      Isaac Jardín

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    1. Irene Frischauf
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    2. Marc Fahrner
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    3. Isaac Jardín
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    Correspondence to Irene Frischauf or Christoph Romanin .

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    1. Depto. Fisiología, University of Extremadura, Cáceres, Spain

      Juan A. Rosado

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    Frischauf, I., Fahrner, M., Jardín, I., Romanin, C. (2016). The STIM1: Orai Interaction. In: Rosado, J. (eds) Calcium Entry Pathways in Non-excitable Cells. Advances in Experimental Medicine and Biology, vol 898. Springer, Cham. https://doi.org/10.1007/978-3-319-26974-0_2

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