The bona fide structure of IgM pentamer and its binding mode with AIM/CD5L molecule

Abstract

Abstract Soluble IgM forms a predominantly pentameric complex that also contains a small polypeptide J chain. While the IgM pentamer has various immune functions to defend against foreign pathogens, it also behaves as a carrier of the circulating apoptosis inhibitor of macrophage (AIM, also called CD5L). The binding to IgM pentamer protects AIM from renal excretion, leading to high serum AIM levels. When AIM dissociates from IgM, it becomes functionally active and facilitates the repair of a variety of diseases including acute kidney injury and hepatocellular carcinoma. Since the precise manner of AIM-IgM pentamer binding remains unknown, we examined the structure using a latest single-particle negative-stain electron microscopy. Surprisingly, the IgM pentamer shapes “one-piece missing” hexagon containing one large gap, which is markedly different from the textbook prediction of a symmetric pentagon model. A single AIM molecule stably fits into the gap, cross-bridging two IgM-Fc through a disulfide bond and a charge-based interaction. We also found that the association of AIM with IgM pentamer not only inactivates AIM but also progresses inflammatory immune-complex formation in certain autoimmune diseases such as IgA nephropathy. Thus, our current findings of the bona fide structure of the AIM/IgM pentamer complex provides an important insight into the releasing mechanism of AIM from IgM, which could be the basis for the development of new therapeutic strategies against multiple diseases, via the increase of active AIM as well as the disruption of immune-complex formation.