2BEG

3D Structure of Alzheimer's Abeta(1-42) fibrils

Summary for 2BEG

• Entry DOI: 10.2210/pdb2beg/pdb
• Descriptor: Amyloid beta A4 protein (1 entity in total)
• Functional Keywords: alzheimer's, fibril, protofilament, beta-sandwich, quenched hydrogen/deuterium exchange, pairwise mutagenesis, protein fibril
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 5
• Total formula weight: 22600.44

Authors

Luhrs, T.,Ritter, C.,Adrian, M.,Riek-Loher, D.,Bohrmann, B.,Dobeli, H.,Schubert, D.,Riek, R. (deposition date: 2005-10-24, release date: 2005-11-22, Last modification date: 2024-05-22)

Primary citation

Luhrs, T.,Ritter, C.,Adrian, M.,Riek-Loher, D.,Bohrmann, B.,Dobeli, H.,Schubert, D.,Riek, R.
3D structure of Alzheimer's amyloid-{beta}(1-42) fibrils.
Proc.Natl.Acad.Sci.Usa, 102:17342-17347, 2005

PubMed Abstract: Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.

PubMed: 16293696
DOI: 10.1073/pnas.0506723102

Experimental method

SOLUTION NMR