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Abstract The Mitochondrial Complex I Assembly (MCIA) complex is essential for the biogenesis of respiratory Complex I (CI), the first enzyme in the respiratory chain, which has been linked to Alzheimer’s disease (AD) pathogenesis. However, how MCIA facilitates CI assembly, and how it is linked with AD pathogenesis, is poorly understood. Here we report the structural basis of the complex formation between the MCIA subunits ECSIT and ACAD9. ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid β-oxidation (FAO) enzyme to a CI assembly factor. We provide evidence that ECSIT phosphorylation downregulates its association with ACAD9 and is reduced in neuronal cells upon exposure to amyloid-β (Aβ) oligomers. These findings advance our understanding of the MCIA complex assembly and suggest a possible role for ECSIT in the reprogramming of bioenergetic pathways linked to Aβ toxicity, a hallmark of AD.

Abstract To save energy and precisely regulate cardiac contractility, cardiac muscle myosin heads are sequestered in an ‘off’ state that can be converted to an ‘on’ state when exertion is increased. The ‘off’ state is equated with a folded-back structure known as the interacting-heads motif (IHM), which is a regulatory feature of all class-2 muscle and non-muscle myosins. We report here the human β-cardiac myosin IHM structure determined by cryo-electron microscopy to 3.6 Å resolution, providing details of all the interfaces stabilizing the ‘off’ state. The structure shows that these interfaces are hot spots of hypertrophic cardiomyopathy mutations that are thought to cause hypercontractility by destabilizing the ‘off’ state. Importantly, the cardiac and smooth muscle myosin IHM structures dramatically differ, providing structural evidence for the divergent physiological regulation of these muscle types. The cardiac IHM structure will facilitate development of clinically useful new molecules that modulate IHM stability.

Membrane lipid composition is a key factor for bacterial stress adaptation. Here, authors show that ViaA and AAA+ ATPase RavA, alter lipid composition and modulate E. coli aminoglycoside sensitivity.

Here the authors report the cryo-EM structure of a triple-mutant of the anti-microbial peptide plectasin, PPI42, assembling in a pH- and concentration dependent manner into helical non-amyloid fibrils. The fibrils formation is reversible, and follows a sigmoidal kinetics. The fibrils adopt a right-handed helical superstructure composed by two protofilaments, stabilized by an outer hydrophobic ring and an inner hydrophobic centre. These findings reveal that α/β proteins can natively assemble into fibrils.

Viruses often subvert the host immune system using molecular decoys to prevent an effective immune response. Here, the authors examine the structural details of the viral decoy receptor GIF and its antagnosim of GM-CSF and IL-2.