Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site.
STIM1 and STIM2 are widely expressed endoplasmic reticulum (ER) Ca(2+) sensor proteins able to translocate within the ER membrane to physically couple with and gate plasma membrane Orai Ca(2+) channels. Although they are structurally similar, we reveal critical differences in the function of the short STIM-Orai-activating regions (SOAR) of STIM1 and STIM2. We narrow these differences in Orai1 gating to a strategically exposed phenylalanine residue (Phe-394) in SOAR1, which in SOAR2 is substituted by a leucine residue. Remarkably, in full-length STIM1, replacement of Phe-394 with the dimensionally similar but polar histidine head group prevents both Orai1 binding and gating, creating an Orai1 non-agonist. Thus, this residue is critical in tuning the efficacy of Orai activation. While STIM1 is a full Orai1-agonist, leucine-replacement of this crucial residue in STIM2 endows it with partial agonist properties, which may be critical for limiting Orai1 activation stemming from its enhanced sensitivity to store-depletion.
1] Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA [2].
Xizhuo
X
Wang
1] Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA [2] Beijing Key Laboratory of Gene Resources and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, P.R. China [3].
Youjun
Y
Wang
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Yandong
Y
Zhou
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Eunan
E
Hendron
1] Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA [2].
Salvatore
S
Mancarella
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Mark D
MD
Andrake
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Brad S
BS
Rothberg
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Jonathan
J
Soboloff
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Donald L
DL
Gill
D000595:Amino Acid Sequence; D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D000071740:ORAI1 Protein; D017386:Sequence Homology, Amino Acid; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2
D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2