Abstract
Stromal interaction molecule 1 (STIM1), the sarcoplasmic reticulum (SR) transmembrane protein, activates store-operated Ca2+ entry (SOCE) in skeletal muscle and, thereby, coordinates Ca2+ homeostasis, Ca2+-dependent gene expression, and contractility. STIM1 occupies space in the junctional SR membrane of the triads and the longitudinal SR at the Z-line. How STIM1 is organized and is retained in these specific subdomains of the SR is unclear. Here, we identified desmin, the major type III intermediate filament protein in muscle, as a binding partner for STIM1 based on a yeast 2-hybrid screen. Validation of the desmin-STIM1 interaction by immunoprecipitation and immunolocalization confirmed that the CC1-SOAR domains of STIM1 interact with desmin to enhance STIM1 oligomerization yet limit SOCE. Based on our studies of desmin-KO mice, we developed a model wherein desmin connected STIM1 at the Z-line in order to regulate the efficiency of Ca2+ refilling of the SR. Taken together, these studies showed that desmin-STIM1 assembles a cytoskeletal-SR connection that is important for Ca2+ signaling in skeletal muscle.
Highlights
Stromal interaction molecule 1 (STIM1) is a multifunctional signaling protein in the sarcoplasmic reticulum/ER (SR/ER) membrane that can interact with many channels, transporters, and signaling molecules [1, 2]
In transmission electron microscopy (TEM) micrographs of STIM1+/lacZ muscle, the β-galactosidase reaction product appeared as a black precipitate, enabling us to define the subcellular localization of STIM1 in intact muscle (Figure 1, C and D)
Macromolecular complexes composed of channels, transporters, and buffers assemble to elicit Ca2+ transients that drive muscle contraction, gene expression, and metabolism
Summary
Stromal interaction molecule 1 (STIM1) is a multifunctional signaling protein in the sarcoplasmic reticulum/ER (SR/ER) membrane that can interact with many channels, transporters, and signaling molecules [1, 2]. Understanding how STIM1-modified target proteins influence Ca2+ signaling in skeletal muscle remains an important yet open question. STIM1 is best recognized as an activator of Orai channels, and together STIM1 and Orai channels form the basic elements for store-operated Ca2+ entry (SOCE) [3,4,5]. STIM1 senses depletion of SR Ca2+ stores and activates Ca2+ entry through Orai channels. Additional STIM1 binding partners exist and include EB1, STING, POST, nuclear transporters, TRPC, PMCA, phospholamban, and SERCAs [6,7,8,9,10]. How STIM1 regulates the function of these targets remains unclear
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