Alexander Myasnikov

Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.

Integrated stress response on the brain During translation, regulation of protein synthesis by phosphorylation of eukaryotic translation initiation factor 2 (eIF2) is a common consequence of diverse stress stimuli, which leads to reprogramming of gene expression. This process, known as the integrated stress response, is one of the most fundamental mechanisms of translational control conserved throughout eukaryotes. It is also a promising therapeutic target in neurodegenerative diseases and traumatic brain injury. Kashiwagi et al. report the cryo–electron microscopy and crystal structures and Kenner et al. report the cryo–electron microscopy structure of the guanine nucleotide exchange factor eIF2B in complex with eIF2 or phosphorylated eIF2. The structures of the eIF2•eIF2B complex reveal that the single phosphorylation modification on eIF2 changes how eIF2 binds to eIF2B and locks this enzyme into an inhibited complex. Science , this issue p. 495 , p. 491