Education:
BS 1987 Chemistry- University of Kansas, Lawrence, Kansas
PhD 1993 Biophysical Chemistry- Yale University, New Haven, CT
Postdoctoral Research Fellowship:
1993-1997 Harvard Medical School and Massachusetts General Hospital
Started at USC: 2005
Research Topics: Protein Chemistry/Enzymology, DNA & RNA, Signal Transduction, Aging, Structural Biology
Research Description
My research focuses on the protein synthesis machinery both as a tool for polypeptide design and as a target that can be probed using chemical means. A key aspect of my lab’s work is peptide and protein design using in vitro selection experiments. Toward this end, we use mRNA display, a technique I conceived and implemented to enable polypeptide design (1) (see figure below). This approach allows my lab to create and sieve more than 10 trillion independent peptide or protein sequences for function, the most of any technique currently available (reviewed in (2)). In applying any design approach, it is optimal if key issues, including affinity, specificity, diversity, structure, dynamics, and biological activity can be addressed in a principled way. My desire has been to build and execute a research program that tackles all of these issues.
My passion is using the tools of chemistry to understand and control biological processes. We have applied our design approach to address biological control, molecular recognition, stability, and dynamics in RNA-peptide complexes (3-10), G proteins (11-13) and G protein coupled receptors (GPCRs) (14). In the future, our efforts should provide new tools for systems biology and leads for therapeutic development.
mRNA display. An mRNA template (black line) covalently attached to puromycin is used to program an in vitro translation reaction. After protein synthesis, the puromycin enters the ribosome in cis to form a covalent mRNA-protein fusion.
We are also very interested to re-engineer the protein synthesis machinery to create unnatural mRNA display libraries. This project, a nanoscale engineering effort, works to merge the power of display selections with the flexibility of combinatorial chemistry. To do this, my lab has worked to extend mRNA display beyond the natural genetic code, in an effort to create new and richly diverse compositions of matter for ligand design, drug discovery, and beyond (15-18) (reviewed in (19)).
In conjunction with our re-engineering efforts, we have become intensely interested in thinking about the ribosome as a target. Our work began with efforts to understand the ribosome's substrate specificity (20-22). These efforts have also yielded unexpected and exciting new reagents that have enabled us to visualize protein synthesis in vivo in T-cells (23) and neurons (24) with spatial and temporal resolution.
Finally, my intellectual interest in evolution and the origin of life has lead me to work on a model for the origin of the ribosome (25) and a proposal for how Darwinian evolution could have begun via coupling genome replication and cellular growth (26).
Overall, my research bridges Chemistry, Biology, and Engineering with the goal of bringing new approaches to molecular design, systems biology, and therapeutics. I have pursued these goals in both formal and informal collaborations at Caltech (J. Alberola-Ila, S. Benzer, P. Bjorkman, D. Dougherty, B. Hay, E. Schuman, A. Varshavsky, A. H. Zewail) and at other universities (S. R. Sprang UTSW, N. Strynadka UBC, J. W. Szostak Harvard Med., L. Jan UCSF).
Selected Publications
Austin RJ, Ja WW, Roberts RW. - Evolution of Class-Specific Peptides Targeting a Hot Spot of the Galphas Subunit. - J Mol Biol [ 2008 ] Jan 18; . PubMed
Millward SW, Fiacco S, Austin RJ, Roberts RW. - Design of cyclic peptides that bind protein surfaces with antibody-like affinity. - ACS Chem Biol [ 2007 ] Sep 21;2(9):625-34 . PubMed
Ja WW, West AP Jr, Delker SL, Bjorkman PJ, Benzer S, Roberts RW. - Extension of Drosophila melanogaster life span with a GPCR peptide inhibitor. - Nat Chem Biol [ 2007 ] Jul;3(7):415-9 . PubMed
Olson CA, Roberts RW. - Design, expression, and stability of a diverse protein library based on the human fibronectin type III domain. - Protein Sci [ 2007 ] Mar;16(3):476-84 . PubMed
Ja WW, Wiser O, Austin RJ, Jan LY, Roberts RW. - Turning G proteins on and off using peptide ligands. - ACS Chem Biol [ 2006 ] Oct 24;1(9):570-4 . PubMed
Wiser O, Qian X, Ehlers M, Ja WW, Roberts RW, Reuveny E, Jan YN, Jan LY. - Modulation of basal and receptor-induced GIRK potassium channel activity and neuronal excitability by the mammalian PINS homolog LGN. - Neuron [ 2006 ] May 18;50(4):561-73 . PubMed
Millward SW, Takahashi TT, Roberts RW. - A general route for post-translational cyclization of mRNA display libraries. - J Am Chem Soc [ 2005 ] Oct 19;127(41):14142-3 . PubMed
Xia T, Wan C, Roberts RW, Zewail AH. - RNA-protein recognition: single-residue ultrafast dynamical control of structural specificity and function. - Proc Natl Acad Sci U S A [ 2005 ] Sep 13;102(37):13013-8 . PubMed
Ja WW, Adhikari A, Austin RJ, Sprang SR, Roberts RW. - A peptide core motif for binding to heterotrimeric G protein alpha subunits. - J Biol Chem [ 2005 ] Sep 16;280(37):32057-60 . PubMed
Ja WW, Olsen BN, Roberts RW. - Epitope mapping using mRNA display and a unidirectional nested deletion library. - Protein Eng Des Sel [ 2005 ] Jul;18(7):309-19 . PubMed
