"I am honored to be able to work with the best and the brightest scientists in the industry and have the opportunity to make contributions to the development of novel therapeutics with the potential to treat significant unmet medical needs."
I came to Genentech as a Postdoctoral Fellow in the Antibody Engineering department. It was fascinating to have an insider’s view into the drug discovery process and witness groundbreaking basic research being performed at the forefront of the biotechnology industry. Thus, when I was offered the opportunity to become a Scientist at Genentech I was thrilled. I initially joined the Protein Chemistry department where my group focused on large molecule drug discovery efforts through protein engineering, purification, and characterization of challenging antigens and therapeutic antibodies. I later joined the Structural Biology department and the focus of my group expanded to include protein structure determination to support both small and large molecule drug discovery. We utilize a combination of protein engineering, X-ray crystallography, and single-particle cryo-electron microscopy (cryo-EM) to enable structure-based drug design for unmet medical needs across oncology, immunology, and neurobiology.
The Genentech Postdoctoral Program offers a unique opportunity to carry out cutting-edge basic research in an industry setting. You are surrounded by leading experts in the field and have access to the latest technology and instrumentation. The discoveries made by Postdoctoral Fellows often are the spark for new therapeutic targets or technology developments. As a former Genentech Postdoctoral Fellow, I have first-hand experience of how transformative the program can be for developing scientists and am excited to now be a mentor involved in training of the next generation of scientists.
Science. 2020;367(6481):1008-1014. DOI: 10.1126/science.aaz5807
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).