Matthew Daugherty

Matt was raised in the town of Succasunna in the great state of New Jersey.  As an undergraduate, he majored in Biochemistry and Neuroscience at Wesleyan University, where he worked in Janice Naegele's lab on DNA-repair mechanisms and their role in apoptosis in the developing cerebral cortex.  Following graduation, he worked in the lab of Andrei Osterman at Integrated Genomics, a small comparative-genomics company in Chicago.  The focus of his research was on the bioinformatic identification and functional characterization of divergent genes in amino acid and Coenzyme A biosynthetic pathways, and it was here that he began to appreciate the diversity of gene function and protein structure across phylogenetic space.  After three years, Matt moved to University of California – San Francisco and began his Ph.D. in Alan Frankel’s lab.  There he worked on the mechanism and structure of HIV Rev, with a particular focus on how adaptability is harnessed to create a complex ribonucleoprotein (RNP) from small, modular protein domains and RNA motifs.  In November 2009, Matt joined Harmit Malik’s lab, where he investigates the evolution of innate immunity to viruses, particularly those viruses known to cause cancer.  Matt is thrilled to be in Seattle and enjoys biking, running, cooking and eating (the former two allowing him to happily pursue to latter two).

Research Interests

Matt is fascinated by how macromolecules are able to specifically recognize each other and form functional complexes in the crowded cellular milieu.  Many years of molecular, biophysical and structural studies have revealed a broad array of strategies that are currently employed by proteins and nucleic acids to create specific molecular recognition interfaces.  Indeed, during his graduate work on HIV Rev, Matt became very interested in how structural adaptability of simple three-dimensional motifs, such as a helix-loop-helix domain, can be employed to define the specificity of binding.  What is not obvious is how the fourth dimension, that of evolutionary time, plays into how recognition surfaces are created and maintained.  One implication of his graduate work was that HIV, and likely many other viruses, use recognition strategies that are highly ‘evolvable’ by being able to tolerate and even benefit from the high viral mutation rate.  In the Malik lab, he is interested in the evolvability of recognition surfaces used by the innate immune system, and will ask what strategies are employed to defeat viruses.  He is particularly interested in using signatures of evolution to gain molecular insight into how viruses are recognized by the innate immune system and how they evade detection.  He is excited to think about these problems from an evolutionary, molecular and structural perspective.

Selected Publications

Daugherty, M.D. & Malik, H.S. Rules of engagement: molecular insights from host-virus arms races.  Annu Rev Genet  In press (2012).

Daugherty, M.D., Liu, B. & Frankel, A.D. Structural basis for cooperative RNA binding and export complex assembly by HIV Rev.  Nat Struct Mol Biol 17, 1337-42 (2009).

Daugherty, M.D., Booth, D.S., Jayaraman, B., Cheng, Y. & Frankel, A.D. HIV Rev response element (RRE) directs assembly of the Rev homooligomer into discrete asymmetric complexes. Proc Natl Acad Sci U S A 107, 12481-86 (2009).

Daugherty, M.D., D'Orso, I. & Frankel, A.D. A solution to limited genomic capacity: using adaptable binding surfaces to assemble the functional HIV Rev oligomer on RNA. Mol Cell 31, 824-34 (2008).

Mills, N.L., Daugherty, M.D., Frankel, A.D. & Guy, R.K. An alpha-helical peptidomimetic inhibitor of the HIV-1 Rev-RRE interaction. J Am Chem Soc 128, 3496-7 (2006).

Calabro, V., Daugherty, M.D. & Frankel, A.D. A single intermolecular contact mediates intramolecular stabilization of both RNA and protein. Proc Natl Acad Sci U S A 102, 6849-54 (2005).

Daugherty, M. et al. Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics. J Biol Chem 277, 21431-9 (2002).

Daugherty, M., Vonstein, V., Overbeek, R. & Osterman, A. Archaeal shikimate kinase, a new member of the GHMP-kinase family. J Bacteriol 183, 292-300 (2001).

Zhou, T., Daugherty, M., Grishin, N.V., Osterman, A.L. & Zhang, H. Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily. Structure 8, 1247-57 (2000).