IgGMedCompAct - Determinants of IgG-mediated complement activation

Project Details

Description

Antibodies (immunoglobulins; IgG) are some of the most important molecules of our immune defense against pathogens and tumor cells. These Y-shaped proteins recognize and tightly bind specific structures on the surface of viruses, bacteria and tumor cells via their two "arms", the so-called Fab regions, and thus mark them for destruction by the immune system. This is possible because the stem of the Y-shaped antibody, the so-called Fc region, then protrudes from the surface of the target cell, and other molecules of the immune system, in particular components of the classical complement pathway, can recognize it. If everything goes right, these molecules bind to the Fc region and to each other, ultimately causing the perforation of the cell membrane thus the elimination of the antibody-tagged target cell.
There are four different subclasses of IgG antibodies (IgG1 - IgG4) in our blood that differ mainly in the length and flexibility of the so-called 'hinge' region (the joint that connects the Fab and Fc regions in the center of the Y). In this project, we will investigate how exactly these IgG subclasses induce the elimination of target cells. Of particular interest is whether a recently discovered mechanism that allows IgG1 molecules to arrange themselves into antibody-hexamers (snowflake-like structures of six Y-shaped antibodies each) after binding to a target cell also applies to the other subclasses (IgG2, IgG3 and IgG4). Hexamerization represents a decisive step in the activation of the classical complement pathway for IgG1, and we will study whether this is the case for the other subclasses as well. In addition, we will elucidate further potential influences on the successful activation of the complement system, such as the binding strength between antibody and target cell and differences in antibody glycosylation (the type of attached sugar molecules).
We will employ a combination of several high-end microscopy techniques (high-speed atomic force microscopy, single-molecule fluorescence microscopy) as well as techniques for quantifying the interactions between antibodies, cell membranes and complement proteins (single-molecule force spectroscopy and quartz-crystal microbalance), which together will allow us to decipher these processes both structurally and dynamically.

Short titleIgGMedCompAct
StatusActive
Effective start/end date01.01.202131.12.2024

Funding agency

  • FWF - Stand-Alone Projects

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