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Title | The first transmembrane region of complement component-9 acts as a brake on its self-assembly. |
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Journal, issue, pages | Nat Commun, Vol. 9, Issue 1, Page 3266, Year 2018 |
Publish date | Aug 15, 2018 |
Authors | Bradley A Spicer / Ruby H P Law / Tom T Caradoc-Davies / Sue M Ekkel / Charles Bayly-Jones / Siew-Siew Pang / Paul J Conroy / Georg Ramm / Mazdak Radjainia / Hariprasad Venugopal / James C Whisstock / Michelle A Dunstone / |
PubMed Abstract | Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC). During MAC assembly, multiple copies of C9 are sequentially recruited to membrane associated ...Complement component 9 (C9) functions as the pore-forming component of the Membrane Attack Complex (MAC). During MAC assembly, multiple copies of C9 are sequentially recruited to membrane associated C5b8 to form a pore. Here we determined the 2.2 Å crystal structure of monomeric murine C9 and the 3.9 Å resolution cryo EM structure of C9 in a polymeric assembly. Comparison with other MAC proteins reveals that the first transmembrane region (TMH1) in monomeric C9 is uniquely positioned and functions to inhibit its self-assembly in the absence of C5b8. We further show that following C9 recruitment to C5b8, a conformational change in TMH1 permits unidirectional and sequential binding of additional C9 monomers to the growing MAC. This mechanism of pore formation contrasts with related proteins, such as perforin and the cholesterol dependent cytolysins, where it is believed that pre-pore assembly occurs prior to the simultaneous release of the transmembrane regions. |
External links | Nat Commun / PubMed:30111885 / PubMed Central |
Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.2 - 3.9 Å |
Structure data | EMDB-7773: The X-ray crystal structure of Complement component-9 reveals that the first trans-membrane region acts as a brake on self-assembly PDB-6cxo: |
Chemicals | ChemComp-ZN: ChemComp-CA: ChemComp-NAG: ChemComp-MG: ChemComp-BMA: ChemComp-HOH: |
Source |
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Keywords | IMMUNE SYSTEM / Immunity / Complex / Complement / MACPF / pore / EM / membrane / transmembrane |