PMC:6093860 / 5261-8246
Annnotations
{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/6093860","sourcedb":"PMC","sourceid":"6093860","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6093860","text":"The X-ray crystal structure of monomeric C9\nThe structure of C9 reveals that the four domains (Thrombospondin type 1 [TSP1], Low density Lipoprotein Receptor Type A [LDLRA], MACPF/CDC and Epidermal growth factor [EGF], Supplementary Fig. 2) are arranged into a globular bundle. Structural comparisons with other MAC proteins (e.g., C8β) reveal that the overall arrangement of domains is similar (Supplementary Fig. 3) except for a striking difference in the position of TMH1 with respect to the core body of the molecule (Fig. 1b, c)14,15.\nFig. 1 The X-ray crystal structure of complement component 9. a The X-ray structure of C9 shown in cartoon in two orientations, rotated 180° apart. The bent β-sheet of the MACPF domain is shown in red with α-helices in blue, TMH1 (green) and TMH2 (yellow). The ancillary domains: TSP1 (purple), LDLRA (pink) and EGF domain (orange). Domain colours also match the colours used to show the domain features in Supplementary Fig. 2. b Cartoon model of C9 with the modelled TMH1 loop (green surface) and N-glycan (PDB ID 1HD4) located on the elongation face of the protein. The key features of the MACPF domain are shown as cartoon and coloured as follows: central β-sheet (red), TMH 1 (green), TMH2 (yellow), HTH (blue). c The C8β structure in the same orientation as C9 showing the TMH1 domain on the docking interface (PDB ID 3OJY)\nIn the structure of C6, C8α, and C8β, TMH1 is arranged such that it does not obviously obstruct binding to the next subunit. Indeed, the structure of the complex between C8α and C8β reveals that the TMH1 of the monomeric C8α is buried within the interface15. The interface of each of these proteins is relatively flat and currently the precise nature of the conformational changes that take place in order for a new molecule to join the assembly remains to be completely understood. In these regards, we and others, have suggested that a structurally conserved Helix-Turn-Helix motif that sits on top of TMH2 represents the major component that must shift during pre-pore assembly11,13,16,17.\nThe monomeric C9 crystal structure reveals that a large proportion of TMH1 (a portion of which is flexible and cannot be resolved in electron density) is located in the centre of the elongation surface where it would be anticipated to block binding of another C9 monomer (Fig. 1b). Interestingly, the flexible region of TMH1 is the least conserved region across all vertebrate species and thus may represent a site under significant evolutionary pressure, for example, as a site of MAC inhibition by bacteria18. In addition, it is notable that TMH1 contains an N-glycan (found in most species) on residue N243 (human equivalent N256), a modification that would add additional bulk to this region. This finding suggests that TMH1 may function to block self-assembly, and that a key event of the interaction between C9 subunits would be a conformational change of TMH1 such that it moves to reveal the C9 elongation surface.","divisions":[{"label":"Title","span":{"begin":0,"end":43}},{"label":"Figure caption","span":{"begin":540,"end":1369}}],"tracks":[]}