Cryomicroscopy reveals the structural basis for a flexible hinge motion in the immunoglobulin M pentamer

Immunoglobulin M (IgM) is the most ancient of the five isotypes of immunoglobulin (Ig) molecules and serves as the first line of defence against pathogens. Here, we use cryo-EM to image the structure of the human full-length IgM pentamer, revealing antigen binding domains flexibly attached to the asymmetric and rigid core formed by the C mu 4 and C mu 3 constant regions and the J-chain. A hinge is located at the C mu 3/C mu 2 domain interface, allowing Fabs and C mu 2 to pivot as a unit both in-plane and out-of-plane. This motion is different from that observed in IgG and IgA, where the two Fab arms are able to swing independently. A biased orientation of one pair of Fab arms results from asymmetry in the constant domain (C mu 3) at the IgM subunit interacting most extensively with the J-chain. This may influence the multi-valent binding to surface-associated antigens and complement pathway activation. By comparison, the structure of the Fc fragment in the IgM monomer is similar to that of the pentamer, but is more dynamic in the C mu 4 domain. Immunoglobulin M (IgM) is the Ig isotype that serves as the first line of host defence during infection. Here, the authors image the full-length IgM pentamer by cryo-EM, revealing the structure and hinge motion of the antigen binding domains.

Automated summary

This study used cryo-EM to investigate the structure of the human full-length IgM pentamer, uncovering flexible antigen binding domains attached to an asymmetric and rigid core. The motion of the Fab arms in IgM is different from IgG and IgA, which may influence its binding to antigens and complement pathway activation.