STIM1 Clusters and Activates CRAC Channels via Direct Binding of a Cytosolic Domain to Orai1

By Chan Young Park, Paul J. Hoover, Franklin M. Mullins, P. Bachhawat, Elizabeth D. Covington, S. Raunser, Thomas Walz, K. Garcia, R. Dolmetsch, R. Lewis. Cell, 2009

968 citations recorded by the source corpus.

SUMMARY Store-operated Ca2+ channels activated by the depletion of Ca2+ from the endoplasmic reticulum (ER) are a major Ca2+ entry pathway in non-excitable cells and are essential for T cell activation and adaptive immunity. Following store depletion, the ER Ca2+ sensor STIM1 and the CRAC channel protein Orai1 redistribute to ER-plasma membrane (PM) junctions, but the fundamental issue of how STIM1 activates the CRAC channel at these sites is unresolved. Here we identify a minimal, highly conserved 107-aa CRAC activation domain (CAD) of STIM1 that binds directly to the N- and C-termini of Orai1 to open the CRAC channel. Purified CAD forms a tetramer that clusters CRAC channels, but analysis of STIM1 mutants reveals that channel clustering is not sufficient for channel activation. These studies establish a molecular mechanism for store-operated Ca2+ entry in which the direct binding of STIM1 to Orai1 drives the accumulation and the activation of CRAC channels at ER-PM junctions.

Subfields: Biochemistry, Cellular and Molecular Neuroscience, Sensory Systems

View Paper: https://www.semanticscholar.org/paper/e49822dbcb5d9fb733ff69dca74ca6416e8bdda6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. R. Lewis
2. Jie Zheng
3. M. Prakriya
4. M. Trudeau

In Sensory Systems

1. R. Lewis
2. M. Prakriya
3. Jie Zheng
4. M. Trudeau
5. Anjana Rao
6. P. Hogan
7. M. Cahalan
8. S. Feske

Citations in the corpus

• Handbook of ion channels (2015, methodology): “In addition to the well-described interaction at the C-terminus of ORAI1, studies using systems of purified components have revealed a second interaction site on ORAI1, located at the N-terminus [40,99].”
• Molecular Basis of Calcium Signaling in Lymphocytes: STIM and ORAI (2010, background): “STIM1 redistributes to puncta in the absence of overexpressed ORAI (19, 29, 31, 33, 99), but overexpressed ORAI does not relocalize appreciably to puncta unless it is coexpressed with STIM (33, 99), indicating that STIM is necessary to recruit ORAI to puncta.”
• The functional network of ion channels in T lymphocytes (2009, background): “Expression of the C-terminus as a cytosolic protein effectively activates CRAC current through the Orai1 (or Orai) channel (94, 99–103), as do fragments of the C-terminus as small as 100 amino acids corresponding to the distal coiled-coil domain (96, 104, 105).”
• Signalling ballet in space and time (2010, neutral): “The STIM oligomers directly bind the CRAC channel protein ORAI1 (also known as CRACM1), which opens the CRAC channe”
• Store-Operated Calcium Channels. (2015, positive): “The requirement for STIM in trapping Orai is shown most clearly by observations that Orai1 alone fails to form puncta but colocalizes in puncta with STIM1- K, which by itself is unable to form puncta without its PBD domain (284).”