PDBsum entry 4zjs

Immune system

PDB id: 4zjs

Contents

Protein chains

206 a.a.

Ligands

4P0 ×3

Waters ×181

PDB id:

4zjs

Name:

Immune system

Title:

Crystal structure of a chimeric acetylcholine binding protein from aplysia californica (ac-achbp) containing the main immunogenic region (mir) from the human alpha 1 subunit of the muscle nicotinic acetylcholine receptor in complex with anatoxin-a.

Structure:

Acetylcholine receptor subunit alpha,soluble acetylcholine receptor,acetylcholine receptor subunit alpha,soluble acetylcholine receptor. Chain: a, b, c, d, e. Engineered: yes

Source:

Homo sapiens, aplysia californica. Human, california sea hare. Organism_taxid: 9606, 6500. Gene: chrna1, achra, chnra. Expressed in: homo sapiens. Expression_system_taxid: 9606

Resolution:

2.23Å R-factor: 0.197 R-free: 0.228

Authors:

T.T.Talley,J.Bobango,J.Wu,J.F.Park,J.Luo,J.Lindsatrom,P.Taylor

Key ref:

J.Luo et al. (2009). Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity. J Neurosci, 29, 13898-13908. PubMed id: 19890000

Date:

29-Apr-15 Release date: 13-May-15

Protein chains

P02708  (ACHA_HUMAN) -  Acetylcholine receptor subunit alpha from Homo sapiens

Seq: 457 a.a.

Struc: 206 a.a.*

Protein chains

Q8WSF8  (Q8WSF8_APLCA) -  Soluble acetylcholine receptor from Aplysia californica

Seq: 236 a.a.

Struc: 206 a.a.*

* PDB and UniProt seqs differ at 156 residue positions (black crosses)

J Neurosci 29:13898-13908 (2009)

PubMed id: 19890000

Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity.

J.Luo, P.Taylor, M.Losen, M.H.de Baets, G.D.Shelton, J.Lindstrom.

ABSTRACT

The main immunogenic region (MIR) is a conformation-dependent region at the extracellular apex of alpha1 subunits of muscle nicotinic acetylcholine receptor (AChR) that is the target of half or more of the autoantibodies to muscle AChRs in human myasthenia gravis and rat experimental autoimmune myasthenia gravis. By making chimeras of human alpha1 subunits with alpha7 subunits, both MIR epitopes recognized by rat mAbs and by the patient-derived human mAb 637 to the MIR were determined to consist of two discontiguous sequences, which are adjacent only in the native conformation. The MIR, including loop alpha1 67-76 in combination with the N-terminal alpha helix alpha1 1-14, conferred high-affinity binding for most rat mAbs to the MIR. However, an additional sequence corresponding to alpha1 15-32 was required for high-affinity binding of human mAb 637. A water soluble chimera of Aplysia acetylcholine binding protein with the same alpha1 MIR sequences substituted was recognized by a majority of human, feline, and canine myasthenia gravis sera. The presence of the alpha1 MIR sequences in alpha1/alpha7 chimeras greatly promoted AChR expression and significantly altered the sensitivity to activation. This reveals a structural and functional, as well as antigenic, significance of the MIR.