STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction.
The receptor-evoked Ca(2+) signal includes activation of the store-operated channels (SOCs) TRPCs and the Orais. Although both are gated by STIM1, it is not known how STIM1 gates the channels and whether STIM1 gates the TRPCs and Orais by the same mechanism. Here, we report the molecular mechanism by which STIM1 gates TRPC1, which involves interaction between two conserved, negatively charged aspartates in TRPC1((639)DD(640)) with the positively charged STIM1((684)KK(685)) in STIM1 polybasic domain. Charge swapping and functional analysis revealed that exact orientation of the charges on TRPC1 and STIM1 are required, but all positive-negative charge combinations on TRPC1 and STIM1, except STIM1((684)EE(685))+TRPC1((639)RR(640)), are functional as long as they are reciprocal, indicating that STIM1 gates TRPC1 by intermolecular electrostatic interaction. Similar gating was observed with TRPC3((697)DD(698)). STIM1 gates Orai1 by a different mechanism since the polybasic and S/P domains of STIM1 are not required for activation of Orai1 by STIM1.
Zeng
Weizhong
W
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yuan
Joseph P
JP
Kim
Min Seuk
MS
Choi
Young Jin
YJ
Huang
Guo N
GN
Worley
Paul F
PF
Muallem
Shmuel
S
D000595:Amino Acid Sequence; D019921:Biotinylation; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating; D007668:Kidney; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology*; D000071740:ORAI1 Protein; D055672:Static Electricity; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; D002118:Calcium