Dynamics and Molecular Interactions of GPI-Anchored CD59

Abstract

CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks MAC pores, the receptor is co-opted by bacterial pore-forming proteins to target human cells. Recent structures of CD59 in complexes with binding partners showed dramatic differences in the orientation of its ectodomain relative to the membrane. Here, we show how GPI-anchored CD59 can satisfy this diversity in binding modes. We present a PyLipID analysis of coarse-grain molecular dynamics simulations of a CD59-inhibited MAC to reveal residues of complement proteins (C6:Y285, C6:R407 C6:K412, C7:F224, C8β:F202, C8β:K326) that likely interact with lipids. Using modules of the MDAnalysis package to investigate atomistic simulations of GPI-anchored CD59, we discover properties of CD59 that encode the flexibility necessary to bind both complement proteins and bacterial virulence factors.

Individualized lipid profile in urine-derived extracellular vesicles from clinical patients with Mycobacterium tuberculosis infections

“…Their loss in red blood cells causes upregulated complement activation ( Colden et al, 2022 ). CD59 was also required by pathogenic bacteria in cholesterol-dependent cytolysins by using virulence factors to punch holes in lipid bilayers ( Parker and Feil, 2005 ; Boyd et al, 2016 ; Voisin et al, 2023 ). In addition, CD14 was also founded as immune activation markers on plasma exosomes from HIV patients ( Chettimada et al, 2018 ).…”

FLIPs: Novel Genetically Encoded Biosensors for Functional Imaging of Cell Signaling by Polarization Microscopy

“…Presence of their respective targets generally increased LD (that is, it increased the absolute values of the observed dichroic logratios), consistent with lowering the orientational freedom of the fluorescent moiety. Interestingly, GP2(1)-meGFP-CD59, a probe of activation of the insulin receptor, showed intracellular localization in absence of its target, despite containing a leader sequence and a GPI anchor (derived from the protein CD59 [27]). In contrast, the probe localized to the cell membrane in cells overexpressing both the probe and IR1.…”