FIGURE 1.

The reference sequence for the human C5 protein was retrieved from Genbank at the NCBI with the accession number NP_001304092. The potential impact of the C5 SNPs on the overall protein structure were investigated using AlphaFold (Varadi et al., 2022) with 3D protein structures visualized using UCSF Chimera (Pettersen et al., 2004) (A). The structure of C5 showing the various domains i.e., macroglobulin (MG)1-MG8. Relative to the published C5 structure (Fredslund et al., 2008), we observed that Val145le mutation is located in the macroglobulin MG2 domain, while the Ser1310Asn is located on the CUB (B). AlphaFold structure prediction of rs17216529:C>T and rs17610:C>T. Inspection of the wild-type (WT) and mutant proteins revealed no significant perturbations to the overall structure. However, subtle changes that may not be detected by AlphaFold may impact on the unstable C5b. The WT molecule for both V145I and S1310N are colored green, while the mutant for V145I is colored red and that of S1310N is colored orange (C). AlphaFold structure prediction of the two SNPs relative to the cleavage site for C5 convertase. Examination of the structure revealed that the SNPs are also distal from the C5 convertase cleavage site. Additionally, the WT structure of both C5 and C5b in the MAC, rs17216529:C>T appeared to be buried, orienting the hydrophobic side chain into the protein. On the other hand, we did not observe a clear interaction partner for rs17216529:C>T neither in the C5 nor MAC structures. However, the mutation is located near the C5b and C7 in the MAC structure (D). AlphaFold structure prediction of the location of mutation on rs17610:C>T. Examination of the C5 protein structure revealed that the mutation is exposed both on the C5 protein, and in the MAC.