The STIM-Orai Pathway
A primary Ca2+ entry pathway in non-excitable cells is determined by the Ca2+ release activated Ca2+ channels. Their two limiting molecular components include the Ca2+-sensor protein STIM1 located in the endoplasmic reticulum and the Orai channel in the p
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The STIM-Orai Pathway The Interactions Between STIM1 and Orai Rainer Schindl, Marc Fahrner, Martin Muik, and Christoph Romanin
4.1
Introduction
The Ca2+-release-activated Ca2+ (CRAC) channel is the best characterized storeoperated channel (Parekh and Putney 2005). Function-based genetic screen by systematic RNA interference (RNAi) has revealed solid evidence that the STIM1 (stromal interaction molecule) and the Orai (also termed CRACM) family represent the key molecular components of CRAC channels (Feske et al. 2006; Liou et al. 2005; Roos et al. 2005; Vig et al. 2006; Zhang et al. 2006). STIM1 acts as an ERlocated Ca2+ sensor (Liou et al. 2005; Roos et al. 2005) by its luminal EF-hand in the N-terminus. It further contains a single transmembrane domain which is followed by a long C-terminal strand essential for interaction with Orai. Each of the three Orai 1–3 proteins includes four transmembrane domains with a cytosolic N and C terminus and forms highly Ca2+-selective channels within the plasma membrane (Prakriya et al. 2006; Schindl et al. 2008; Vig et al. 2006; Yeromin et al. 2006). The respective Orai channels are distinct in their inactivation profiles and 2-aminoethoxydiphenyl borate (2-APB) sensitivity (DeHaven et al. 2007; Lis et al. 2007). STIM1 exhibits a tubular distribution within the ER membrane at resting state (Grigoriev et al. 2008; Honnappa et al. 2009). Upon store-depletion it oligomerizes and translocates into punctate clusters close to the plasma membrane (Baba et al. 2006; Liou et al. 2007, 2005; Luik et al. 2006; Mercer et al. 2006; Soboloff et al. 2006; Wu et al. 2006; Xu et al. 2006; Zhang et al. 2005), thereby activating Orai/ CRAC channels.
R. Schindl (*) • M. Fahrner • M. Muik • C. Romanin (*) Institute of Biophysics, University of Linz, Linz, Austria e-mail: [email protected]; [email protected] K. Groschner et al. (eds.), Store-operated Ca2+ entry (SOCE) pathways, DOI 10.1007/978-3-7091-0962-5_4, # Springer-Verlag/Wien 2012
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Essential Structures within STIM1 that Mediate Interaction with and Activation of Orai
The luminal N-terminus of STIM1 contains a canonical and a hidden EF-hand as well as a sterile-alpha motif (SAM) (Stathopulos et al. 2008, 2009). The initial trigger for STIM1 oligomerization is represented by its N-terminal EF-hand. Upon store-depletion the EF-hand looses bound Ca2+ and consequently allows for aggregation of STIM1 proteins (Liou et al. 2005; Luik et al. 2006; Roos et al. 2005; Wu et al. 2006), as described in more detail in Chap.2. A luminal Ca2+ drop initiates STIM1 oligomerization via destabilization of the entire EF-SAM entity (Stathopulos et al. 2008). In line, a STIM1 deletion mutant lacking the whole C-terminus also oligomerizes, yet its aggregates are unstable (Covington et al. 2010). The cytosolic C-terminus includes three coiled-coil domains, a serine/prolineand a lysine-rich region (Baba et al. 2006; Huang et al. 2006; Liou et al. 2005; Smyth et al. 2006) (Fig. 4.1a). Within the cytosolic part of STIM1 th
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