Spatial arrangement of proteins in planar and curved membranes by PPM 3.0

Abstract

Cellular protrusions, invaginations, and many intracellular organelles have strongly curved membrane regions. Transmembrane and peripheral membrane proteins that induce, sense, or stabilize such regions cannot be properly fitted into a single flat bilayer. To treat such proteins, we developed a new method and a web tool, PPM 3.0, for positioning proteins in curved or planar, single or multiple membranes. This method determines the energetically optimal spatial position, the hydrophobic thickness, and the radius of intrinsic curvature of a membrane-deforming protein structure by arranging it in a single or several sphere-shaped or planar membrane sections. In addition, it can define the lipid-embedded regions of a protein that simultaneously spans several membranes or determine the optimal position of a peptide in a spherical micelle. The PPM 3.0 web server operates with 17 types of biological membranes and 4 types of artificial bilayers. It is publicly available at https://opm. phar.umich.edu/ppm_server3. PPM 3.0 was applied to identify and characterize arrangements in membranes of 128 proteins with a significant intrinsic curvature, such as BAR domains, annexins, Piezo, and MscS mechanosensitive channels, cation-chloride cotransporters, as well as mitochondrial ATP synthases, calcium uniporters, and TOM complexes. These proteins form large complexes that are mainly localized in mitochondria, plasma membranes, and endosomes. Structures of bacterial drug efflux pumps, AcrAB-TolC, MexAB-OrpM, and MacAB-TolC, were positioned in both membranes of the bacterial cell envelop, while structures of multimeric gap-junction channels were arranged in two opposed cellular membranes.

Specific interactions of peripheral membrane proteins with lipids: what can molecular simulations show us?

“…That said, incorporating mesoscale resolutions into studies along with CG and AA [ 134 ] can potentially be very powerful, especially for looking at such phenomena as membrane curvature [ 135 ]. Similarly, continuum models can be used to rapidly predict PMP association with regions of curvature via the PPM 3.0 webserver ( https://opm.phar.umich.edu/ppm_server3; [ 136 ]).…”

Spatiotemporal stop-and-go dynamics of the mitochondrial TOM core complex correlates with channel activity

“…Our findings are consistent with the “tether model” 45 , where an intermembrane protein anchor domain (here Tom22) limits lateral diffusion, as observed for a large number of α-helical membrane proteins 44 , 45 , 50 – 53 . Since the TOM-CC complex bends the outer mitochondrial membrane locally towards the intermembrane space with an average radius of about 140 Å 54 , the anchor domains of the two Tom22 subunits should easily be able to dock with other proteins in the mitochondrial intermembrane space and the mitochondrial inner membrane. It will be interesting to study as to whether the mechanostimulated conformational change of the TOM-CC observed in vitro can be confirmed in intact mitochondria.…”

Multifaceted membrane binding head of the SARS-CoV-2 spike protein

“… Lomize et al, 2012 ; A.L. Lomize, Todd, and Pogozheva, 2022 ). The latter is available online to predict the spatial position of a protein structure on a fluid anisotropic solvent slab that represents a membrane-like environment.…”

“…The proximities of modified residues to the membrane binding elements identified here in the structures was assessed by visual inspection of models of the lipid bilayer complexes as predicted by PPM 3.0 (A.L. Lomize, Todd, and Pogozheva, 2022 ). The regulatory impact of small modifications is generally limited to distances corresponding to ∼5 residues, as these bounds were previously useful for identifying positions that, when phosphorylated or metabolite-modified, modulate specific membrane recognition by protein residues acting as PIP-stops ( Kervin and Overduin, 2021 ) and MET-stops majority of membrane binding ( Kervin et al, 2021 ).…”