Polymerization of IgA and IgM: roles of Cys309/Cys414 and the secretory tailpiece.
We have investigated how the secretory tailpiece (tp), Cys414 and the amino acids flanking Cys414 or Cys309 are involved in regulating the different polymerization of IgM and IgA to pentamers and dimers/monomers, respectively. Whereas changing the tp of IgM to that of IgA has little effect on IgM polymerization, introducing the mu tp to IgA leads to the formation of larger than wild-type IgA polymers, including pentamers and hexamer. This shows that the secretory tp can differentially regulate polymerization depending on the heavy chain context. Cys414, which is engaged in intermonomeric disulfide bonds in IgM, is not crucial for the difference in IgM and IgA polymerization; IgM with a C414S mutation forms more large polymers than IgA. Also, IgA with IgM-like mutations in the five amino acids flanking Cys309, which is homologous to Cys414, oligomerize similarly as IgA wild type. Thus, IgA appears to have an inherent tendency to form monomers and dimers that is partially regulated by the tp, while the Cys309 region has only a minor effect. We also show that complement activation by IgM is sensitive to alterations in the polymeric structure, while IgA is inactive in classical complement activation even for polymers such as pentamers and hexamers.
Sørensen
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Department of Molecular Cell Biology, University of Oslo, Norway.
Sundvold
V
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Michaelsen
T E
TE
Sandlie
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I
D000595:Amino Acid Sequence; D000818:Animals; D003167:Complement Activation / Q000276:immunology; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007070:Immunoglobulin A / Q000737:chemistry / Q000378:metabolism*; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D007075:Immunoglobulin M / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D012635:Secretory Component / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
D007070:Immunoglobulin A; D007141:Immunoglobulin Fc Fragments; D007075:Immunoglobulin M; D011108:Polymers; D012635:Secretory Component; D003545:Cysteine