Structure of human complement C8, a precursor to membrane attack

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Complement component C8 is essential for forming the membrane attack complex (MAC), a key antibacterial immune effector.
• C8 initiates membrane penetration and orchestrates MAC pore formation, but its subunit organization remains structurally undefined.
• Existing high-resolution structures of C8 subunits lack information on intersubunit organization crucial for MAC assembly.

Purpose of the Study:

• To determine the structure of the C8 heterotrimer and elucidate how its subunits are organized to facilitate MAC assembly.
• To provide structural insights into the functional mechanisms of C8 during MAC formation.

Main Methods:

• Determined the structure of C8 using electron microscopy.
• Fitted the C8α-MACPF-C8γ co-crystal structure into the electron microscopy density.
• Incorporated a homology model for C8β-MACPF into the density map.

Main Results:

• The study presents the overall structure of the C8 heterotrimer.
• Demonstrated the accessibility of the C8γ protrusion, which is involved in MAC assembly.
• Showed that the C8α-MACPF region, responsible for membrane insertion upon activation, is also accessible.

Conclusions:

• The determined structure provides a framework for understanding C8 function in MAC assembly.
• The accessibility of key functional regions (C8γ protrusion and C8α-MACPF) offers insights into C8's role in membrane attack.
• This structural information is vital for comprehending the antibacterial mechanisms of the complement system.