PDBsum entry 1iga

Immunoglobulin

PDB id: 1iga

Contents

Protein chains

475 a.a.*

214 a.a.*

* C-alpha coords only

References listed in PDB file

Key reference

Title

The FAB and fc fragments of iga1 exhibit a different arrangement from that in igg: a study by x-Ray and neutron solution scattering and homology modelling.

Authors

M.K.Boehm, J.M.Woof, M.A.Kerr, S.J.Perkins.

Ref.

J Mol Biol, 1999, 286, 1421-1447. [DOI no: 10.1006/jmbi.1998.2556]

PubMed id

10064707

Abstract

Human immunoglobulin A (IgA) is an abundant antibody that mediates immune protection at mucosal surfaces as well as in plasma. The IgA1 isotype contains two four-domain Fab fragments and a four-domain Fc fragment analogous to that in immunoglobulin G (IgG), linked by a glycosylated hinge region made up of 23 amino acid residues from each of the heavy chains. IgA1 also has two 18 residue tailpieces at the C terminus of each heavy chain in the Fc fragment. X-ray scattering using H2O buffers and neutron scattering using 100 % 2H2O buffers were performed on monomeric IgA1 and a recombinant IgA1 that lacks the tailpiece (PTerm455). The radii of gyration RG from Guinier analyses were similar at 6.11-6.20 nm for IgA1 and 5.84-6.16 nm for PTerm455, and their cross-sectional radii of gyration RXS were also similar. The similarity of the RG and RXS values suggests that the tailpiece of IgA1 is not extended outwards in solution. The IgA1 RG values are higher than those for IgG, and the distance distribution function P(r) showed two distinct peaks, whereas a single peak was observed for IgG. Both results show that the hinge of IgA1 results in an extended Fab and Fc arrangement that is different from that in IgG. Automated curve-fit searches constrained by homology models for the Fab and Fc fragments were used to model the experimental IgA1 scattering curves. A translational search to optimise the relative arrangement of the Fab and Fc fragments held in a fixed orientation resembling that in IgG was not successful in fitting the scattering data. A new molecular dynamics curve-fit search method generated IgA1 hinge structures to which the Fab and Fc fragments could be connected in any orientation. A search based on these identified a limited family of IgA1 structures that gave good curve fits to the experimental data. These contained extended hinges of length about 7 nm that positioned the Fab-to-Fab centre-to-centre separation 17 nm apart while keeping the corresponding Fab-to-Fc separation at 9 nm. The resulting extended T-shaped IgA1 structures are distinct from IgG structures previously determined by scattering and crystallography which have Fab-to-Fab and Fab-to-Fc centre-to-centre separations of 7-9 nm and 6-8 nm, respectively. It was concluded that the IgA1 hinge is structurally distinct from that in IgG, and this results in a markedly different antibody structure that may account for a unique immune role of monomeric IgA1 in plasma and mucosa.

Figure 1.
Figure 1. Schematic diagram of the Ig fold domains in human IgA1 and IgG1. Each heavy chain contains the V[H], C[H]1, C[H]2 and C[H]3 domains, and each light chain contains the V[L]and C[L]domains, each of which is represented by a rectangle. The four-domain Fab fragments are linked to the four-domain Fc fragment by a 23 residue hinge in IgA1. The C terminus of each IgA1 heavy chain contains an 18 residue tailpiece (broken line). The hinge of IgG1 is one residue shorter and there is no tailpiece. Each Ig fold contains a conserved internal Cys-Cys disulphide bridge (S-S). The C[H]1 domain of IgA1 has an additional disulphide bridge between Cys196-Cys220. The heavy and light chains of IgA1 are linked between Cys133 in the C[H]1 domain, and the C-terminal Cys residue of the light chain. The heavy and light chains of IgG1 are linked by a Cys residue in the hinge and the C-terminal Cys residue of the light chain. In IgA1, Cys241 and Cys242 in the hinge and Cys299 and Cys301 in the C[H]2 domain form intra and inter-heavy chain disulphide bridges. In IgG1, two Cys residues in the hinge form two inter-chain bridges. In IgA1, Cys311 on the C[H]2 domain and Cys471 in the tailpiece are shown free. IgA1 has two N-linked oligosaccharide sites on β-strand B of the C[H]2 domain and on the tailpiece (•). That on the C[H]2 domain of IgA1 is at a different position to that on the C[H]2 domain of IgG1 which occupies a central cavity in the IgG1 Fc structure and which is conserved in the other human Ig classes. IgA1 also has five O-linked oligosaccharide sites in the hinge (○) which are not present in IgG1. PTerm455 is a recombinant IgA1 molecule which lacks the tailpiece.

Figure 4.
Figure 4. Distance distribution functions P (r) for PTerm455, human IgA1 and bovine IgG2. (a) PTerm455 using neutron data measured at 2.4 mg/ml, for which M1 and M2 occur at 4.0 nm and 8.7 nm, respectively, and L is 20 nm. (b) IgA1 using X-ray data measured at 2.1 mg/ml, for which the peaks M1 and M2 occur at 3.7 nm and 8.9 nm, respectively, and the length L is 21 nm. (c) Bovine IgG2 using neutron data [Mayans et al 1995], for which M occurs at 5.4 to 5.7 nm, and L is 16 nm.

The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 286, 1421-1447) copyright 1999.

Secondary reference #1

Title

Molecular structures from low angle X-Ray and neutron scattering studies.

Authors

S.J.Perkins, A.W.Ashton, M.K.Boehm, D.Chamberlain.

Ref.

Int J Biol Macromol, 1998, 22, 1. [DOI no: 10.1016/S0141-8130(97)00088-3]

PubMed id

9513811

Secondary reference #2

Title

Analogy and solution scattering modelling: new structural strategies for the multidomain proteins of complement, Cartilage and the immunoglobulin superfamily.

Authors

S.J.Perkins, C.G.Ullman, N.C.Brissett, D.Chamberlain, M.K.Boehm.

Ref.

Immunol Rev, 1998, 163, 237-250.

PubMed id

9700514