PDBsum entry 6dcv

Immune system

PDB id: 6dcv

Contents

Protein chains

220 a.a.

226 a.a.

Ligands

GOL ×3

Waters ×637

PDB id:

6dcv

Name:

Immune system

Title:

Crystal structure of human anti-tau antibody cbtau-27.1

Structure:

Light chain of cbtau27.1 fab. Chain: l, a. Engineered: yes. Heavy chain of cbtau-27.1 fab. Chain: h, b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell: hek 293-f. Expression_system_cell: hek 293-f

Resolution:

1.90Å R-factor: 0.188 R-free: 0.229

Authors:

X.Zhu,H.Zhang,I.A.Wilson

Key ref:

A.Apetri et al. (2018). A common antigenic motif recognized by naturally occurring human V_H5-51/V_L4-1 anti-tau antibodies with distinct functionalities. Acta Neuropathol Commun, 6, 43. PubMed id: 29855358

Date:

08-May-18 Release date: 06-Jun-18

Protein chains

P01834  (IGKC_HUMAN) -  Immunoglobulin kappa constant from Homo sapiens

Seq: 107 a.a.

Struc: 220 a.a.

Protein chains

P01857  (IGHG1_HUMAN) -  Immunoglobulin heavy constant gamma 1 from Homo sapiens

Seq: 399 a.a.

Struc: 226 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Acta Neuropathol Commun 6:43 (2018)

PubMed id: 29855358

A common antigenic motif recognized by naturally occurring human V_H5-51/V_L4-1 anti-tau antibodies with distinct functionalities.

A.Apetri, R.Crespo, J.Juraszek, G.Pascual, R.Janson, X.Zhu, H.Zhang, E.Keogh, T.Holland, J.Wadia, H.Verveen, B.Siregar, M.Mrosek, R.Taggenbrock, J.Ameijde, H.Inganäs, M.van Winsen, M.H.Koldijk, D.Zuijdgeest, M.Borgers, K.Dockx, E.J.M.Stoop, W.Yu, E.C.Brinkman-van der Linden, K.Ummenthum, K.van Kolen, M.Mercken, S.Steinbacher, D.de Marco, J.J.Hoozemans, I.A.Wilson, W.Koudstaal, J.Goudsmit.

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 V_H5-51/V_L4-1 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 V_H5-51 and V_L4-1 recognizes a common Pro-X_n-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.