Trends in Biochemical Sciences
Conformation-dependent antibodies target diseases of protein misfolding
Section snippets
A generic structural motif for amyloid fibrils
Early X-ray diffraction studies on fibrils indicated that amyloid fibrils have a ‘cross-β’ structure in which the backbone hydrogen bonding is parallel to the fibril axis 1, 2. There is increasing awareness that these aggregates are highly ordered β-sheet lattices that represent a generic quaternary motif of intermolecular hydrogen-bonded polypeptide chains that is not commonly encountered in native protein structures. Solid-state NMR, together with site-directed spin labeling and electron
Common pathways of amyloid aggregation
If misfolded proteins ultimately assemble into a common fibril structure, it is reasonable to suspect that their assembly pathways might be similar (Figure 2). The unfolded or misfolded protein acquires the ability to self-assemble into higher-order structures [12], including non-covalent dimers, trimers, tetramers and larger oligomers that can be observed by gel filtration, SDS gel electrophoresis and electron and atomic force microscopy. For Aβ, these soluble oligomers have the properties of
Antibodies that distinguish native and misfolded conformations
The variety of oligomer sizes and fibril structures, coupled with the implication that they might represent the prime suspects in degenerative disease, presents us with an opportunity to understand the mechanistic details underlying these diseases. It also presents us, however, with the challenge of determining the conformational status of misfolded proteins in vivo or under physiological conditions in a complex mixture of proteins. For a long time, the conformational status of a protein has
Conformation-dependent antibodies that recognize generic structural features
There is increasing evidence that amyloid fibrils and soluble oligomeric intermediates have a common structure and pathway of aggregation. Some of this evidence has come from the discovery of antibodies that recognize generic epitopes on all types of amyloid fibril [44] and soluble oligomer [45], independently of their specific amino acid sequences.
Concluding remarks
Conformation-dependent antibodies are an important tool for analyzing protein misfolding and aggregation, as well as for targeting degenerative diseases that are caused by protein misfolding. They provide a facile means of both dissecting different steps in the aggregation pathway and determining the mechanism of aggregation. They also provide a way in which to assess the role of amyloid conformers in the disease process that would be difficult or impossible to achieve by other means. The fact
References (52)
Supramolecular structure in full-length Alzheimer's β-amyloid fibrils: evidence for a parallel β-sheet organization from solid- state nuclear magnetic resonance
Biophys. J.
(2002)Structural and dynamic features of Alzheimer's Aβ peptide in amyloid fibrils studied by site-directed spin labeling
J. Biol. Chem.
(2002)Structural organization of α-synuclein fibrils studied by site-directed spin labeling
J. Biol. Chem.
(2003)Solid State NMR Reveals a pH-dependent antiparallel β-sheet registry in fibrils formed by a β-amyloid peptide
J. Mol. Biol.
(2004)Protein misfolding, evolution and disease
Trends Biochem. Sci.
(1999)Surfactant properties of Alzheimer's Aβ peptides and the mechanism of amyloid aggregation
J. Biol. Chem.
(1994)Observation of metastable Aβ amyloid protofibrils by atomic force microscopy
Chem. Biol.
(1997)Amyloid β-protein fibrillogenesis. Detection of a protofibrillar intermediate
J. Biol. Chem.
(1997)Studies on the in vitro assembly of Aβ1–40: implications for the search for Aβ fibril formation inhibitors
J. Struct. Biol.
(2000)The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer's disease pathology
J. Biol. Chem.
(1996)
Intracellular Aβ1–42 aggregates stimulate the accumulation of stable, insoluble amyloidogenic fragments of the amyloid precursor protein in transfected cells
J. Biol. Chem.
Antibody-mediated resolution of light chain-associated amyloid deposits
Am. J. Pathol.
A conformation change in the carboxyl terminus of Alzheimer's Aβ1–40 accompanies the transition from dimer to fibril as revealed by fluorescence quenching analysis
J. Biol. Chem.
The yeast prion [PSI+]: molecular insights and functional consequences
Adv Protein Chem
Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction
Neuron
X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-β conformation
Proc. Natl. Acad. Sci. U. S. A.
Synthetic peptide homologous to β protein from Alzheimer disease forms amyloid-like fibrils in vitro
Proc. Natl. Acad. Sci. U. S. A.
Propagating structure of Alzheimer's β-amyloid(10–35) is parallel β-sheet with residues in exact register
Proc. Natl. Acad. Sci. U. S. A.
Multiple quantum solid-state NMR indicates a parallel, not antiparallel, organization of β-sheets in Alzheimer's β-amyloid fibrils
Proc. Natl. Acad. Sci. U. S. A.
Tau paired helical filaments from Alzheimer's disease brain and assembled in vitro are based on β-structure in the core domain
Biochemistry
Template-assisted filament growth by parallel stacking of tau
Proc. Natl. Acad. Sci. U. S. A.
Amyloid fibril formation by Aβ16–22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR
Biochemistry
Models of amyloid seeding in Alzheimer's disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins
Annu. Rev. Biochem.
Kinetic theory of fibrillogenesis of amyloid β-protein
Proc. Natl. Acad. Sci. U. S. A.
Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins
Proc. Natl. Acad. Sci. U. S. A.
Fibrils formed in vitro from α-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid
Biochemistry
Cited by (141)
Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies
2021, International Journal of Biological MacromoleculesRational affinity maturation of anti-amyloid antibodies with high conformational and sequence specificity
2021, Journal of Biological ChemistryAn "epitomic" analysis of the specificity of conformation dependent, anti-Aß amyloid monoclonal antibodies
2021, Journal of Biological ChemistryCitation Excerpt :Sequences beginning at [IL]VF occur at approximately 93% of the total sequences recognized by mOC108. Twenty-six of the monoclonals clearly recognize an Aß-related epitope that is located in the amino terminal (1–14) or central (7, 15–28) third of the molecule or both (Fig. 2). Ten antibodies (mOC1, mA11-09, mOC15, mOC22, mOC23, mOC64, mOC98, mOC107, mA11-118, and mA11-204) all have epitopes centered on residues 1 to 5 DAEFR.
Passive immunotherapies targeting Aβ and tau in Alzheimer's disease
2020, Neurobiology of DiseaseNature-inspired design and evolution of anti-amyloid antibodies
2019, Journal of Biological ChemistryMenadione sodium bisulfite inhibits the toxic aggregation of amyloid-β(1–42)
2018, Biochimica et Biophysica Acta - General Subjects