Skip to main content
. Author manuscript; available in PMC: 2022 Feb 1.
Published in final edited form as: Am J Med Sci. 2020 Oct 8;361(2):176–194. doi: 10.1016/j.amjms.2020.10.003

Figure 2. Structure of Human IgA1 and O-glycosylation of the IgA1 Hinge Region.

Figure 2.

IgA exists in several molecular forms in the circulation: monomers, dimers, trimers, large polymers, secretory IgA, as well as bound in immune complexes. The figure depicts an IgA1 monomer. Each heavy chain has a N-linked (attached to a nitrogen molecule in asparagine) glycan (carbohydrate) side chains (orange) in the second and third constant-region domains (Cα2 and Cα3) and clustered O-glycans (attached to an oxygen molecule in serine or threonine; blue) in the hinge region between the first and second constant-region domains (Cα1 and Cα2). This hinge region in the IgA1 molecule has 9 threonine and serine residues to some of which a glycan can attach. The composition and number of the O-glycans vary considerably among the IgA1 molecules in an individual, creating microheterogeneity for the hinge region structure. The IgA1 hinge region usually has 3 to 6 O-linked glycans. When compared with healthy individuals, patients with IgAN have more of circulating IgA1 molecules with less galactose (galactose-deficient IgA1). The monomer depicted has five O-linked glycans at each of the two hinge regions. (A) O-linked glycan synthesis proceeds in a stepwise fashion, starting with attachment of N-acetylgalactosamine to a hinge-region serine or threonine amino acid. (B) The glycan is typically extended by attachment of galactose to N-acetylgalactosamine by the core 1 β1,3-galactosyltransferase (C1GALT1) enzyme whose activity is stabilized by a molecular chaperone, C1GALT1C1 (also called COSMC). (C, D) Sialic acid (N-acetylneuraminic acid) can be attached to N-acetylgalactosamine, galactose, or both. (E) If sialic acid is attached to N-acetylgalactosamine prior to attachment of galactose, subsequent attachment of galactose is not possible. An imbalance in the activities or expression of specific glycosyltransferases in IgA1-producing cells of patients with IgAN accounts for the increased production of galactose-deficient O-linked glycans in the IgA1 hinge region. Cα denotes constant-region domain on alpha heavy chain; CL, constant-region domain on light chain; VH, variable region on heavy chain; and VL, variable region on light chain. Fab, fragment antigen-binding; Fc, fragment crystallizable region, GalNAc, N-acetylgalactosamine; Gal, galactose; Pro, proline; Val, valine; Ser, serine; Thr, threonine; Cys, cysteine.