Advances in cryo-EM that have shaped mechanistic models of membrane-attack-complex assembly and regulation

The complement system is a blood-based immune network that plays a crucial role in fighting infection and maintaining immune homeostasis. The membrane attack complex (MAC) is a pore assembled from complement proteins that creates holes in cells when the immune system is activated. Over the last ten years, advances in cryo-electron microscopy (cryo-EM) have enabled key molecular insights into how the MAC assembles, remodels membranes and is regulated. These new tools revealed the inherent flexibility of complement complexes. By adapting computational approaches that disentangle diverse conformations, these studies have provided detailed mechanisms for MAC activity that could underpin novel complement-targeted therapeutics. Now accelerated by AI-driven image analysis and advances in structural cell biology, the next revolution in cryo-EM offers new opportunities to understand the cellular consequences of immune activation.