title: Initial activation of STIM1, the regulator of store-operated calcium entry.
abstract: Physiological Ca(2+) signaling in T lymphocytes and other cells depends on the STIM-ORAI pathway of store-operated Ca(2+) entry. STIM1 and STIM2 are Ca(2+) sensors in the endoplasmic reticulum (ER) membrane, with ER-luminal domains that monitor cellular Ca(2+) stores and cytoplasmic domains that gate ORAI channels in the plasma membrane. The STIM ER-luminal domain dimerizes or oligomerizes upon dissociation of Ca(2+), but the mechanism transmitting activation to the STIM cytoplasmic domain was previously undefined. Using Tb(3+)-acceptor energy transfer, we show that dimerization of STIM1 ER-luminal domains causes an extensive conformational change in mouse STIM1 cytoplasmic domains. The conformational change, triggered by apposition of the predicted coiled-coil 1 (CC1) regions, releases the ORAI-activating domains from their interaction with the CC1 regions and allows physical extension of the STIM1 cytoplasmic domain across the gap between ER and plasma membrane and communication with ORAI channels.
authors.affiliation: La Jolla Institute for Allergy & Immunology, La Jolla, California, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhou
authors.forename: Prasanna
authors.initials: P
authors.lastname: Srinivasan
authors.forename: Shiva
authors.initials: S
authors.lastname: Razavi
authors.forename: Sam
authors.initials: S
authors.lastname: Seymour
authors.forename: Paul
authors.initials: P
authors.lastname: Meraner
authors.forename: Aparna
authors.initials: A
authors.lastname: Gudlur
authors.forename: Peter B
authors.initials: PB
authors.lastname: Stathopulos
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ikura
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Hogan
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D000071740:ORAI1 Protein; D011487:Protein Conformation; D015202:Protein Engineering; D012394:Rosaniline Dyes; D013050:Spectrometry, Fluorescence; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008562:Membrane Glycoproteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D012394:Rosaniline Dyes; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; C024757:Coomassie brilliant blue R