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Updated: May 2, 2026
Membrane-SPINE: A Biochemical Tool to Identify Protein-protein Interactions of Membrane Proteins In Vivo
Published on: November 8, 2013
Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense
Michael A Hadders1, Dennis X Beringer, Piet Gros
1Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands.
Abstract:
Membrane attack is important for mammalian immune defense against invading microorganisms and infected host cells. Proteins of the complement membrane attack complex (MAC) and the protein perforin share a common MACPF domain that is responsible for membrane insertion and pore formation. We determined the crystal structure of the MACPF domain of complement component C8alpha at 2.5 angstrom resolution and show that it is structurally homologous to the bacterial, pore-forming, cholesterol-dependent cytolysins. The structure displays two regions that (in the bacterial cytolysins) refold into transmembrane beta hairpins, forming the lining of a barrel pore. Local hydrophobicity explains why C8alpha is the first complement protein to insert into the membrane. The size of the MACPF domain is consistent with known C9 pore sizes. These data imply that these mammalian and bacterial cytolytic proteins share a common mechanism of membrane insertion.
Insights
Mammalian immune proteins like complement membrane attack complex (MAC) and perforin use a shared MACPF domain for pore formation. Structural analysis reveals homology with bacterial cytolysins, suggesting a common membrane insertion mechanism.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- Membrane attack is crucial for mammalian immunity against pathogens and infected cells.
- Proteins involved in membrane attack, such as the complement membrane attack complex (MAC) and perforin, share a common MACPF domain responsible for pore formation.
- Understanding the structural basis of MACPF domain function is key to deciphering immune defense mechanisms.
Purpose of the Study:
- To determine the crystal structure of the MACPF domain of complement component C8alpha.
- To investigate the structural homology between the mammalian MACPF domain and bacterial pore-forming proteins.
- To elucidate the mechanism of membrane insertion employed by complement proteins.
Main Methods:
- X-ray crystallography was used to determine the 2.5 angstrom resolution crystal structure of the C8alpha MACPF domain.
- Structural comparison and homology modeling were employed to relate the C8alpha MACPF domain to bacterial cytolysins.
- Analysis of protein structure and hydrophobicity was performed to understand membrane interaction.
Main Results:
- The crystal structure of the C8alpha MACPF domain was determined at 2.5 angstrom resolution.
- The C8alpha MACPF domain shows significant structural homology to bacterial, pore-forming, cholesterol-dependent cytolysins.
- The structure reveals regions capable of refolding into transmembrane beta hairpins, consistent with pore lining, and local hydrophobicity explains C8alpha's initial membrane insertion.
Conclusions:
- Mammalian MACPF domains and bacterial cytolysins share a common structural framework and likely a conserved mechanism for membrane insertion and pore formation.
- The structural insights provide a molecular basis for understanding how complement proteins initiate membrane attack.
- This study bridges the understanding of innate immune mechanisms and bacterial pathogenesis through shared protein structures.
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