Professor, Medicinal Chemistry
PH: 206 685 2468
- Ph.D., 1987, University of California at San Francisco
- PharmD, 1983, University of California at San Francisco
- B.A., Biochemistry (cum Laude), 1979, San Francisco State University
Biophysical Virology. Our laboratory is interested in the molecular mechanisms of viral assembly in the double-stranded DNA viruses. Similar mechanisms have been proposed for many of these viruses, from the bacteriophages to mammalian viruses including adenovirus and the herpesvirus groups. Terminase enzymes are common to all of these viruses and are responsible for specific recognition of viral DNA, "maturation" of the genome in preparation for packaging, specific recognition of an empty capsid, and translocation of viral DNA into the confines of the capsid interior. We have developed a defined in vitro system where an infectious virus can be assembled from purified proteins and commercially available lambda DNA. We couple detailed enzyme kinetic analyses (steady-state and pre-steady-state) with biophysical characterization of protein•protein and protein•DNA interactions (CD & fluorescence spectroscopy, analytical ultracentrifugation, and quantitative gel shift & DNase footprinting, etc.) to characterize the structure and function of the packaging motor complex and the process of DNA packaging. We further interrogate the kinetic and thermodynamic features of a remarkable capsid expansion step that accompanies genome packaging.
Designer Viral Nanoparticles. Therapeutic and diagnostic nanoparticles fall into two broad categories: viral and nonviral, each with their respective strengths and weaknesses. We have harnessed the lambda capsid system for the construction of "designer" nanoparticles for use as therapeutic and diagnostic (theragnostic) agents. For delivery applications, scaffold proteins can be modified, either by fusion with protein "cargo" or by specific chemical ligation with small molecule drugs, polynucleotides, or synthetic macromolecules. In addition, the surface of the particle is symmetrically decorated with an external capsid protein that assembles as trimer spikes at the 140 three-fold icosahedral axes. The decoration protein can be specifically conjugated with protein and/or synthetic moieties in defined ratios to enhance cellular targeting/uptake of the particle, to avoid immune surveillance, or alternatively, to enhance immune response to the capsid as a defined antigenic particle. These engineered viral nanoparticles can be tailored in specific ways to afford a delivery vehicle with defined surface characteristics and containing multiple cargos for both diagnostic and therapeutic applications.
HIV Env Nanodiscs. This project seeks to utilize nanodisc technology to assemble HIV Env trimers in a defined lipid bilayer and to characterize the structure and function of the antigenic trimeric spikes. Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS). The HIV envelope glycoproteins (Env) present the primary features exposed on the viral surface that could be recognized by neutralizing antibodies. Despite heroic efforts, the development of broadly neutralizing antibodies to HIV have been uniformly unsuccessful, most likely because soluble Env constructs fail to faithfully recapitulate the native conformation of the membrane-bound Env spike at the virus surface. Phospholipid nanodiscs are derived from high-density lipoprotein (HDL) particles in humans; they provide stable model membranes with a "native-like" lipid bilayer into which membrane propteins can be embedded in a native and functional form. We assemble Env-Nanodiscs in vitro to provide a novel platform to study Env structure and function and provide the foundation for future studies that would utilize this innovative immunogen for HIV vaccine development.
- Nurmemmedov E, Castelnovo M, Medina E, Catalano CE, and Evilevitch A. "Challenging Packaging Limits and Infectivity of Phage Lambda." J Mol Biol., 415:263-273; ePub Nov 15 (2012).
- Andrews BT, Catalano CE. "The enzymology of a viral genome packaging motor is influenced by the assembly state of the motor subunits." Biochemistry 51(46):9342-53; ePub Nov 7 (2012).
- Medina E, Nakatani E, Kruse S, and Catalano CE. "Thermodynamic Characterization of Viral Procapsid Expansion into a Functional Capsid Shell." J Mol Biol., 418:167-180; ePub Feb 23 (2012).
- Chang JR, Andrews BT, and Catalano CE. "Energy Independent Helicase Activity of a Viral Genome Packaging." Biochemistry, 51:391-400; ePub Dec 30 (2011).
- Medina EM, Andrews BT, Nakatani E, and Catalano CE. "The Bacteriophage Lambda gpNu3 Scaffolding Protein is an Intrinsically Disordered and Biologically Functional Procapsid Assembly Catalyst." J Mol Biol., 412:723-736; ePub Jul 29 (2011).
- Tsay JM, Sippy J, delToro D, Andews BT, Draper B, Rao V, Catalano CE, Feiss M, Smith DE. "Mutations Altering a Structurally Conserved Loop-Helix-Loop Region of a Viral Packaging Motor Change DNA Translocation Velocity and Processivity." J Biol Chem. 285(31):24282-9 (2010).
- Yang Q, Maluf NK, and Catalano CE, "Packaging of a Unit-Length Viral Genome: The Role of Nucleotides and the gpD Decoration Protein in Stable Nucleocapsid Assembly in Bacteriophage Lambda." Journal of Molecular Biology 383:1113-1122 (2008).
- Nurmemmedov E, Castelnovo M, Catalano CE, Evilevitch A, "Biophysics of viral infectivity: matching genome length with capsid size." Quarterly Reviews of Biophysics 40: 327-356 (2007).
- Gaussier H, Yang Q, and Catalano CE, "Building a virus from scratch: assembly of an infectious virus using purified components in a rigorously defined biochemical assay system." Journal of Molecular Biology 357:1154-1166 (2006).