Marissa Matsumoto

The focus of my lab’s basic research is engineering and structural characterization of immunoglobulins (Ig) and their specific interaction with antigens and cellular receptors. We are particularly interested in secreted IgA and IgM, which play vital roles in protecting the approximately 400 m2 of human mucosal epithelium from pathogenic invasion. Both IgA and IgM contain 18-residue tailpiece extensions on their heavy chains that bestow polymer-forming capabilities. IgA can form dimers and higher order polymers, with oligomerization requiring a 137-residue joining chain (JC) with no known structural homologs. IgM similarly forms pentamers when assembled with the JC. IgA and IgM oligomers undergo a process of transcytosis, crossing the epithelium, to reach the external secretions and perform their protective functions. Transcytosis of IgA and IgM is initiated through binding to the basolaterally expressed polymeric immunoglobulin receptor (pIgR), an interaction that requires the presence of the tailpieces and JC. Upon transcytosis, proteolytic cleavage releases the secretory component (SC) of the receptor, which forms a disulfide bond to the Igs leading to the formation of secretory IgA and IgM (sIgA and sIgM). In this mature form, sIgA and sIgM perform their anti-microbial, neutralization and protective functions. Although high-resolution crystal structures of the SC and monomeric IgA- and IgM-Fcs have been determined, atomic resolution structures of the mysterious JC and sIgA and sIgM remained unsolved for nearly half a century after their discovery. We recently determined the structures of the IgA-Fc and IgM-Fc linked by the JC and in complex with the SC of pIgR (Kumar N, et al. 2020 Science DOI: 10.1126/science.aaz5807; Kumar N, et al. 2020 bioRxiv DOI: 10.1101/2020.09.10.291138). Our structures reveal for the first time the architecture of the JC, elucidate the specificity of pIgR for polymeric Igs, and suggest a mechanism for JC-templated Ig oligomerization. These structures open the door to engineering possibilities for the development of potential therapeutic IgAs and IgMs.

My lab is also interested in engineering antibodies that recognize complex ubiquitin post-translational modifications (PTM). Ubiquitination is a highly conserved PTM where the C-terminus of ubiquitin is linked through an isopeptide bond to a lysine residue of a substrate protein. Ubiquitin contains seven different lysines and a free N-terminus through which additional ubiquitin subunits can be linked to generate polyubiquitin chains. Therefore, eight different homotypic polyubiquitin chain linkages can be formed. As a Postdoctoral Fellow, I engineered polyubiquitin linkage-specific antibodies that have helped advance the study of the cellular ubiquitination code. Recently it has been demonstrated that the ubiquitination code is much more complex than originally anticipated and the existence of heterotypic polyubiquitin chains containing more than one linkage have been identified. These include both mixed chains, where each ubiquitin subunit has only one lysine involved in a linkage, and branched chains, where ubiquitin subunits have two or more lysines involved in linkages. My lab has further expanded the ubiquitin PTM antibody toolbox to include a bispecific antibody to recognize K11/K48-branched polyubiquitin chains which revealed a novel role in protein quality control (Yau RG, et al. 2017 Cell DOI: 10.1016/j.cell.2017.09.040).

• Genentech, Postdoctoral Fellowship in Antibody Engineering – 2007-2011
• Washington University in St. Louis, Ph.D. in Molecular Cell Biology – 2007
• Northwestern University, B.A. in Biology – 2000

• Genentech gRED Innovation Fund Award – 2017