STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels

By Guo N. Huang, W. Zeng, J. Y. Kim, Joseph P. Yuan, Linhuang Han, S. Muallem, P. Worley. Nature Cell Biology, 2006

663 citations recorded by the source corpus.

Receptor-evoked Ca2+ signalling involves Ca2+ release from the endoplasmic reticulum, followed by Ca2+ influx across the plasma membrane. Ca2+ influx is essential for many cellular functions, from secretion to transcription, and is mediated by Ca2+-release activated Ca2+ (Icrac) channels and store-operated calcium entry (SOC) channels. Although the molecular identity and regulation of Icrac and SOC channels have not been precisely determined, notable recent findings are the identification of STIM1, which has been indicated to regulate SOC and Icrac channels by functioning as an endoplasmic reticulum Ca2+ sensor, and ORAI1 (ref. 7) or CRACM1 (ref. 8) — both of which may function as Icrac channels or as an Icrac subunit. How STIM1 activates the Ca2+ influx channels and whether STIM1 contributes to the channel pore remains unknown. Here, we identify the structural features that are essential for STIM1-dependent activation of SOC and Icrac channels, and demonstrate that they are identical to those involved in the binding and activation of TRPC1. Notably, the cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, Icrac and TRPC1 channels even when native STIM1 is depleted by small interfering RNA. Activity of STIM1 requires an ERM domain, which mediates the selective binding of STIM1 to TRPC1, 2 and 4, but not to TRPC3, 6 or 7, and a cationic lysine-rich region, which is essential for gating of TRPC1. Deletion of either region in the constitutively active STIM1D76A yields dominant-negative mutants that block native SOC channels, expressed TRPC1 in HEK293 cells and Icrac in Jurkat cells. These observations implicate STIM1 as a key regulator of activity rather than a channel component, and reveal similar regulation of SOC, Icrac and TRPC channel activation by STIM1.

Subfields: Ecology, Evolution, Behavior and Systematics, Molecular Biology, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/48bfe53cc9020d1766a96f8199051cc6475bee6e

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In Molecular Biology

1. R. Lewis
2. P. Hogan
3. Jie Zheng
4. M. Trudeau
5. Anjana Rao

In Sensory Systems

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2. Jie Zheng
3. M. Trudeau
4. Anjana Rao
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Citations in the corpus

• STIM1 Clusters and Activates CRAC Channels via Direct Binding of a Cytosolic Domain to Orai1 (2009, neutral): “…C-terminal polybasic domain, an ERM-like domain, and a serine-proline-rich domain, have been implicated in the activation of Orai1, but their specific roles and interactions in these localization events are not understood (Baba et al., 2006; Huang et al., 2006; Li et al., 2007; Liou et al., 2007).”
• Handbook of ion channels (2015, background): “They also found that deletion of a large stretch of this domain that includes the coiled-coil motifs (amino acids 231–535) eliminated constitutive activity of this fragment [41].”
• Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI (2010, background): “Expression of the STIM1 cytoplasmic region alone, divorced from the luminal domain and the transmembrane tether, activates endogenous CRAC channels in Stim1−/− T cells, Jurkat T cells, and RBL cells (34, 36, 111, 140).”
• TRP Channels (2012, neutral): “forming segment of the calcium release-activated calcium channel, Orai1 (159, 317).”
• Store-Operated Calcium Channels. (2015, neutral): “Deletion of the PBD prevents redistribution but not oligomerization, consistent with the idea that oligomerization triggers conformational changes that expose the PBD to the PM (154, 198, 284).”