Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery

We provide an overview of the Ca2+ signaling pathways that are involved in mediating sarco/endoplasmic reticulum stored Ca2+ release, Store-operated Ca2+ entry, and mitochondrial Ca2+ uptake, as well as pinpoint multiple levels of crosstalk between these pathways

Megan Noble; Qi-Tong Lin; Christian Sirko; Jacob A. Houpt; Matthew J. Novello; Peter B. Stathopulos

2020

Scholarcy highlights

  • Regulating cytosolic calcium ion levels is fundamental for cellular life
  • Over the past ~15 years, a number of protein structures involved in regulating cytosolic and stored Ca2+ have been elucidated. This surge of structural information has been fueled by high throughput proteomic and genomic approaches that have solved decades old mysteries regarding the molecular identities of proteins that are involved in mediating ubiquitous cellular processes, such as Store-operated Ca2+ entry and mitochondrial Ca2+ uptake, and by improving technologies aimed at revealing protein structures, such as cryo-electron microscopy, solution nuclear magnetic resonance, and X-ray crystallography
  • Two aspects of stromal interaction molecules/Orai and mitochondrial Ca2+ uniporter signaling make this approach to identifying drugs appealing: these proteins function in large complexes that are amenable to intermolecular fluorescence-resonance energy transfer monitoring and STIMs are known to undergo large conformational changes, making them amenable to intramolecular FRET monitoring
  • We provide a simple strategy for applying high-resolution structural knowledge of proteins as a starting point to drug development
  • Several key protein structures are available that inform on the mechanisms regulating the SOCE-mitochondrial Ca2+ signaling axis, providing several possible initiating points to protein structure-based drug design
  • The elucidation of Ca2+ signaling protein structures is vital for understanding the fundamental mechanisms underlying cellular processes that are integral to life and death
  • The structural information can provide an entry point for the development of tools and therapeutics targeting these pathways

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