Complement C1q‐target proteins recognition is inhibited by electric moment effectors

Abstract

Classical complement pathway is an important innate immune mechanism, which is usually triggered by binding of C1q to immunoglobulins, pentraxins and other target molecules. Although the activation of the classical pathway is crucial in the host defence, its undesirable and uncontrolled activation can lead to tissue damage. Thus, understanding the molecular basis of complement activation and its inhibition are of great biomedical importance. Recently, we proposed a mechanism for target recognition and classical pathway activation by C1q, which is likely governed by calcium-controlled reorientation of macromolecular electric moment vectors. Here we sought to define the mechanism of C1q inhibition by low molecular weight disulphate compounds that bind to the globular (gC1q) domain, using experimental, computational docking and theoretical modelling approaches. Our experimental results demonstrate that betulin disulphate (B2S) and 9,9-bis(4'-hydroxyphenyl)fluorene disulphate (F2S) inhibit the interaction of C1q and its recombinant globular modules with target molecules IgG1, C-reactive protein (CRP) and long pentraxin 3 (PTX3). In most C1q-inhibitor docked complexes, there is a reduction of electric moment scalar values and similarly altered direction of electric/dipole moment vectors. This could explain the inhibitory effect by impaired electrostatic steering, lacking optimal target recognition and formation of functional complex. In the presence of the inhibitor, the tilt of gC1q domains is likely to be blocked by the altered direction of the electric moment vector. Thus, the transition from the inactive (closed) towards the active (open) conformation of C1q (i.e. the complement activation signal transmission) will be impaired and the cascade initiation disrupted. These results could serve as a starting point for the exploration of a new form of 'electric moment inhibitors/effectors'.

Heme Interacts with C1q and Inhibits the Classical Complement Pathway

“…In contrast, the binding to mCRP and pCRP is driven by favorable changes in equilibrium entropy. These data are supported by previous observations indicating that the binding sites for IgG and CRP may overlap but are not identical (30,43,44). The observed differences in the binding mechanism of native C1q also reflect the different nature of the target proteins.…”

Heme interacts with C1Q and inhibits the classical complement pathway

“…In contrast, the binding to mCRP and pCRP is driven by favorable changes in equilibrium entropy. These data are supported by previous observations indicating that the binding sites for IgG and CRP may overlap but are not identical (30,43,44). The observed differences in the binding mechanism of native C1q also reflect the different nature of the target proteins.…”

“…Moreover, synthetic heterocyclic compounds such as bisphenol disulfates, sulfated steroids, and triterpenoids also inhibit the classical complement pathway at the level of C1q (47,48). Two of these compounds, betulin disulfate and 9,9-bis(4Ј-hydroxyphenyl) fluorene disulfate, were studied in detail (43). They bind to gC1q and inhibit its interaction with IgG1 and CRP by modulating the electrostatic properties of the protein, reducing the scalar values, and altering the orientation of the electric moment vectors of gC1q.…”

Complement activation by phospholipids: the interplay of factor H and C1q

“…Targets are recognized by proteins of the three activation pathways, C1q from the classical pathway, Mannan binding lectin (MBL) and ficolins from the lectin pathway and C3, factors H and B and properdin from the alternative pathway. Complement activation by the classical pathway occurs when the first component of complement, C1, binds, mainly via charge interactions (Roumenina et al, 2007) to immune complexes (containing IgG or IgM) or directly to a non-immunoglobulin target surface. The antibody-independent activation of C1 has been described for a wide variety of organisms and substances (Sim and Malhotra, 1994) including DNA (Agnello et al, 1969), Gram-negative bacteria (Clas et al, 1989), retroviruses (Cooper et al, 1976), amyloids and prions , anionic phospholipids (Marjan et al, 1994) and synthetic materials (Rybak-Smith et al, 2010).…”