6GK8

Crystal structure of anti-tau antibody dmCBTAU-28.1, double mutant (S32R, E35K) of CBTAU-28.1, in complex with Tau peptide A7731 (residues 52-71)

Summary for 6GK8

• Entry DOI: 10.2210/pdb6gk8/pdb
• Related: 5ZV3 6DCV 6DCW
• Descriptor: HUMAN FAB ANTIBODY FRAGMENT OF CBTAU-28.1(S32R;E35K), TAU PEPTIDE A7731 (RESIDUES 52-71), CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: antibody, fab, tau, complex, immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 50367.25

Authors

Steinbacher, S.,Mrosek, M.,Juraszek, J. (deposition date: 2018-05-18, release date: 2018-06-13, Last modification date: 2024-10-16)

Primary citation

Apetri, A.,Crespo, R.,Juraszek, J.,Pascual, G.,Janson, R.,Zhu, X.,Zhang, H.,Keogh, E.,Holland, T.,Wadia, J.,Verveen, H.,Siregar, B.,Mrosek, M.,Taggenbrock, R.,Ameijde, J.,Inganas, H.,van Winsen, M.,Koldijk, M.H.,Zuijdgeest, D.,Borgers, M.,Dockx, K.,Stoop, E.J.M.,Yu, W.,Brinkman-van der Linden, E.C.,Ummenthum, K.,van Kolen, K.,Mercken, M.,Steinbacher, S.,de Marco, D.,Hoozemans, J.J.,Wilson, I.A.,Koudstaal, W.,Goudsmit, J.
A common antigenic motif recognized by naturally occurring human VH5-51/VL4-1 anti-tau antibodies with distinct functionalities.
Acta Neuropathol Commun, 6:43-43, 2018

PubMed Abstract: Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated V5-51/V4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of V5-51 and V4-1 recognizes a common Pro-X-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

PubMed: 29855358
DOI: 10.1186/s40478-018-0543-z

Experimental method

X-RAY DIFFRACTION (2.85 Å)