Conformation-dependent antibodies target diseases of protein misfolding

doi:10.1016/j.tibs.2004.08.009

Trends in Biochemical Sciences

Volume 29, Issue 10, October 2004, Pages 542-547

https://doi.org/10.1016/j.tibs.2004.08.009 Get rights and content

Many degenerative diseases are fundamentally associated with aging and the accumulation of misfolded proteins as amyloid fibrils. Although such diseases are associated with different proteins, they share several pathological features. These similarities might be due to underlying commonalities in the pathway of aggregation and the structures of the various aggregation products. Because protein misfolding is thought to be central to the pathological state, it is essential to be able to distinguish such pathological states from native and non-pathological states, especially in vivo or in complex mixtures. Conformation-dependent antibodies that specifically recognize misfolded proteins are proving to be useful tools for examining the mechanisms of amyloid formation and for clarifying the roles of various misfolded states in pathogenesis. The common structures and mechanisms hold promise for the development of broad-spectrum drugs and vaccines that will be effective for the treatment of many of these diseases.

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

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Trends in Biochemical Sciences

Conformation-dependent antibodies target diseases of protein misfolding

Section snippets

A generic structural motif for amyloid fibrils

Common pathways of amyloid aggregation

Antibodies that distinguish native and misfolded conformations

Conformation-dependent antibodies that recognize generic structural features

Concluding remarks

Biophys. J.

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

Trends Biochem. Sci.

J. Biol. Chem.

Chem. Biol.

J. Biol. Chem.

J. Struct. Biol.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

Adv Protein Chem

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

Amyloid fibril formation by Aβ_16–22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR

Diffusible, nonfibrillar ligands derived from Aβ_1–42 are potent central nervous system neurotoxins