Structure and assembly of calcium homeostasis modulator proteins
The biological membranes of many cell types contain large pore channels through which a wide variety of ions and metabolites permeate. Examples include connexin, innexin and pannexin, which form gap junctions and/or bona fide cell surface channels. The most recently identified large pore channels are the calcium homeostasis modulators (CALHMs) through which ions and ATP permeate in a voltage dependent manner to control neuronal excitability, taste signaling and pathologies of depression and Alzheimer's disease. Despite such critical biological roles, the structures and patterns of their oligomeric assembly remain unclear. Here, we reveal the structures of two CALHMs, chicken CALHM1 and human CALHM2, by single particle cryo electron microscopy (cryo EM) which show novel assembly of the four transmembrane helices into channels of octamers and undecamers, respectively. Furthermore, molecular dynamics simulations suggest that lipids can favorably assemble into a bilayer within the larger CALHM2 pore, but not within CALHM1, demonstrating the potential correlation between pore size, lipid accommodation and channel activity. Cryo EM structures of the calcium homeostasis modulator channels chicken CALHM1 and human CALHM2 reveal that they function as octa and undecamers, respectively. Molecular dynamics simulations suggest that a lipid bilayer can form within the CALHM2 pore.
Nature Structural Molecular Biology