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. 2014 Mar 19;289(19):13243–13258. doi: 10.1074/jbc.M114.557231

FIGURE 8.

FIGURE 8.

Catabody defense system (CADSys). A, regions of TTR with the best sequence similarity to Aβ, gp120, and Protein A. 1, TTR and Aβ42 (e = 9.4). 2 and 3, TTR and gp120 (e = 2.6 and 6.4, respectively). 4, TTR and Protein A (e = 23). Dots, identities. Red, conservative substitutions. Alignments were obtained with BLAST using the BLOSUM62 matrix and expect (e) threshold of 1,000. The sequence similarities are weak (large e values, p > 0.05 for all alignments). The indicated Protein A region, but not the Aβ42 and gp120 regions, has a β-turn-forming propensity. The TTR region aligned with Protein A also tends to form a β-turn. Substrate regions with the greatest β-turn forming propensity are as follows: TTR, 95–101 and 109–115; Aβ, 5–11 and 23–29; gp120, 146–147e and 362–368 (HXB2 numbering); Protein A, 259–265 and 299–305. Accession numbers are as follows: human TTR, AAA73473; human Aβ42, NP000475; HIV gp120MN, AF075721; S. aureus Protein A, 88193823. B, the catabody defense system concept is based on discovery of innate antibodies that clear pathogenic amyloids and microbial superantigens. Because amyloid removal is predicted to confer a survival advantage to the organism, the emergence of germ line anti-amyloid catabodies in immune evolution is proposed. Superantigen epitopes leave microbes susceptible to innate catabodies and reversibly binding antibodies. However, superantigens help microbes evade acquired immunity, and microbial superantigen-host immune system interactions probably reflect competing factors favoring survival of microbes and the host. C, amyloid protein conservation in humans and jawed fish of the Batoidea superorder (Leucoraja erinacea and Narke japonica). Top, TTR; bottom, Aβ42. Dots, amino acid identities. Red, conservative substitutions. The full-length human TTR and Aβ42 sequences are shown. Accession numbers are as follows: L. erinacea TTR, CV221819; N. japonica amyloid precursor protein 699 residues 601–642, BAA24230.1. Jawed fish are the first extant organisms with human antibody-like molecules.