7OW1

Crystal Structure of TAP01 in complex with amyloid beta peptide

Summary for 7OW1

• Entry DOI: 10.2210/pdb7ow1/pdb
• Descriptor: Amyloid-beta precursor protein, TAP01 family antibody heavy chain, TAP01 family antibody light chain, ... (5 entities in total)
• Functional Keywords: alzheimer's disease, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 48446.81

Authors

Hall, G.,Cowan, R.,Carr, M.D. (deposition date: 2021-06-16, release date: 2022-06-29, Last modification date: 2024-10-16)

Primary citation

Bakrania, P.,Hall, G.,Bouter, Y.,Bouter, C.,Beindorff, N.,Cowan, R.,Davies, S.,Price, J.,Mpamhanga, C.,Love, E.,Matthews, D.,Carr, M.D.,Bayer, T.A.
Discovery of a novel pseudo beta-hairpin structure of N-truncated amyloid-beta for use as a vaccine against Alzheimer's disease.
Mol Psychiatry, 27:840-848, 2022

PubMed Abstract: One of the hallmarks of Alzheimer's disease (AD) are deposits of amyloid-beta (Aβ) protein in amyloid plaques in the brain. The Aβ peptide exists in several forms, including full-length Aβ1-42 and Aβ1-40 - and the N-truncated species, pyroglutamate Aβ3-42 and Aβ4-42, which appear to play a major role in neurodegeneration. We previously identified a murine antibody (TAP01), which binds specifically to soluble, non-plaque N-truncated Aβ species. By solving crystal structures for TAP01 family antibodies bound to pyroglutamate Aβ3-14, we identified a novel pseudo β-hairpin structure in the N-terminal region of Aβ and show that this underpins its unique binding properties. We engineered a stabilised cyclic form of Aβ1-14 (N-Truncated Amyloid Peptide AntibodieS; the 'TAPAS' vaccine) and showed that this adopts the same 3-dimensional conformation as the native sequence when bound to TAP01. Active immunisation of two mouse models of AD with the TAPAS vaccine led to a striking reduction in amyloid-plaque formation, a rescue of brain glucose metabolism, a stabilisation in neuron loss, and a rescue of memory deficiencies. Treating both models with the humanised version of the TAP01 antibody had similar positive effects. Here we report the discovery of a unique conformational epitope in the N-terminal region of Aβ, which offers new routes for active and passive immunisation against AD.

PubMed: 34776512
DOI: 10.1038/s41380-021-01385-7

Experimental method

X-RAY DIFFRACTION (1.4 Å)