Exceptional Amyloid β Peptide Hydrolyzing Activity of Nonphysiological Immunoglobulin Variable Domain Scaffolds

Abstract

Following initial noncovalent binding of antigen, some Igs proceed to catalyze its chemical transformation. Examples of Ig-catalyzed reactions include hydrolysis of polypeptide antigens (2, 3), hydrolysis of nucleic acids (4, 5), and various acyl transfer reactions of other antigen classes (6). Proteolytic Igs that utilize serine protease-like covalent hydrolytic pathways have been described (7,8). Serine protease-like catalytic triads have been identified in the V domains of Igs by site-directed mutagenesis and crystallography (9, 10). The catalytic mechanism involves nucleophilic attack on the electrophilic carbonyl of peptide bonds. Electrophilic phosphonate diesters originally developed as covalent probes for the nucleophilic site of serine proteases bind catalytic Igs irreversibly and inhibit their catalytic activity (7,11,12). The strength of Igantigen noncovalent binding often exceeds that of enzyme-substrate binding. An important limitation holding back the application of catalytic Igs for clearance of undesirable antigens is that their catalytic rate constants (turnover number; k cat ) are small compared with enzymes. Evidently, Ig adaptive selection is geared toward noncovalent immune complexation (the ground state stabilization step), and the ability of Igs to recognize the high energy transition state complex that must be stabilized to accelerate chemical reactions is limited. This is supported by observations that IgMs, the first and least diversified Ig class produced during B cell differentiation, express superior catalytic rate constants than IgGs produced by the cells at later stages of their adaptive differentiation (12).Accumulation of amyloid ␤ peptide (A␤) 2 aggregates in the brain is thought to be a central contributor to neurodegenera-* This work was supported, in whole or in part, by National Institutes of Health Grant R01AG025304. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank TM /EBI Data Bank with accession number(s) FJ231714, FJ231715, FJ231716, FJ231717, FJ231718, FJ231719, FJ231720, FJ231721, FJ231722, and FJ231723

Amyloid beta: structure, biology and structure-based therapeutic development

“…The hormone melatonin may be effective against amyloid by interacting with dimers of the soluble Aβ peptide and inhibiting their aggregation [293][294][295] . The cannabinoid HU-210 [296] has been shown to prevent Aβ-induced inflammation [297] .…”

Constitutive Production of Catalytic Antibodies to a Staphylococcus aureus Virulence Factor and Effect of Infection

“…The models obtained from the two servers were mostly superimposable (root mean square deviation values of the models for the C-␣ position and side chains, respectively, 1.47 and 2.45 Å). Potential nucleophilic dyads in the RosettaAntibody model of scFV 1H2 were identified as described (34,35), defined as sites in which the hydroxyl oxygen atoms of Ser or Thr are located within 4 Å from a possible general base (the imidazole nitrogen atoms of His, the ␤/␥-carboxylate oxygen atoms of Glu/Asp, the ⑀-amino nitrogen atom of Lys, or the -amino/imino nitrogen atoms of Arg). Potential nucleophilic triads contained an additional second general base within hydrogen bonding distance of the first general base.…”

The human genome is composed of viral DNA: Viral homologues of the protein products cause Alzheimer's disease and others via autoimmune mechanisms.

“…While certain beta-amyloid autoantibodies may trigger a hazardous immune response, potentially destroying beta-amyloid containing cells, others possess catalytic properties and are less likely to provoke an immune response 58,71 . These antibodies target the beta-amyloid peptide within the regions depicted in Fig 6. Interestingly three cancer-inducing viruses target these regions (Epstein-Barr, Hepatitis B and the papillomavirus).…”