Comparing Multifunctional Viral and Eukaryotic Proteins for Generating Scission Necks in Membranes

• Published in: ACS nano 2024-06, Vol.18 (24), p.15545-15556
• Main Authors: Alimohamadi, Haleh, Luo, Elizabeth Wei-Chia, Gupta, Shivam, de Anda, Jaime, Yang, Rena, Mandal, Taraknath, Wong, Gerard C. L.
• Format: Article
• Language: English
• Subjects: Cell Membrane - chemistry; Cell Membrane - metabolism; Dynamins - chemistry; Dynamins - metabolism; Influenza A virus - metabolism; Scattering, Small Angle; Viral Matrix Proteins - chemistry; Viral Matrix Proteins - metabolism; Viroporin Proteins
• ISSN: 1936-0851; 1936-086X; 1936-086X
• DOI: 10.1021/acsnano.4c00277

Deterministic formation of membrane scission necks by protein machinery with multiplexed functions is critical in biology. A microbial example is M2 viroporin, a proton pump from the influenza A virus that is multiplexed with membrane remodeling activity to induce budding and scission in the host membrane during viral maturation. In comparison, the dynamin family constitutes a class of eukaryotic proteins implicated in mitochondrial fission, as well as various budding and endocytosis pathways. In the case of Dnm1, the mitochondrial fission protein in yeast, the membrane remodeling activity is multiplexed with mechanoenzyme activity to create fission necks. It is not clear why these functions are combined in these scission processes, which occur in drastically different compositions and solution conditions. In general, direct experimental access to changing neck sizes induced by individual proteins or peptide fragments is challenging due to the nanoscale dimensions and influence of thermal fluctuations. Here, we use a mechanical model to estimate the size of scission necks by leveraging small-angle X-ray scattering structural data of protein–lipid systems under different conditions. The influence of interfacial tension, lipid composition, and membrane budding morphology on the size of the induced scission necks is systematically investigated using our data and molecular dynamic simulations. We find that the M2 budding protein from the influenza A virus has robust pH-dependent membrane activity that induces nanoscopic necks within the range of spontaneous hemifission for a broad range of lipid compositions. In contrast, the sizes of scission necks generated by mitochondrial fission proteins strongly depend on lipid composition, which suggests a role for mechanical constriction.