Dr. SEEMA MATTOOAssociate Professor
PROFESSIONAL FACULTY RESEARCH
(Biochemistry, Signal Transduction, and Microbiology) Investigation of Fic domain containing proteins in Cellular Signaling. Post-translational modification of proteins is a common theme in signal transduction.
The year 2009 introduced a new family of enzymes, defined by the presence of a 'Fic' (filamentation induced by c-AMP) domain. Fic domains consist of an HxFxx[G/A]N[G/K]R motif within an alpha helical core, with the histidine being essential for catalytic activity, and are conserved from bacteria to humans. Since our initial findings describing Fic proteins as adenylyltransferases (ATases) that inhibit RhoGTPase function, the field of Fic-mediated post-translational modifications has become a central player in signal transduction. This family of evolutionarily conserved proteins utilizes ATP, GTP, CTP, UTP, as well as their derivatives to adenylylate, uridinylate, as well as phosphocholinate substrates, thereby altering cellular signaling. <span style="text-decoration: underline;">Our goal is to biochemically characterize these proteins with the aim of identifying their substrates and role(s) in prokayotic and eukaryotic cellular signaling processes.</span>
Post-translational modification of proteins is a common theme in signal transduction. Research in the Mattoo lab focuses on a newly discovered family of evolutionarily conserved proteins that are defined by the presence of a ‘Fic domain’ . These Fic proteins utilize nucleotides and nucleotide derivatives to post-translationally modify their substrates, thereby altering cellular signaling. Specifically, in 2009, we and others reported that bacterial toxins containing the Fic domain could utilize ATP to add an AMP (adenosine mono-phosphate) to RhoGTPases 1,2 . This adenylylation event (sometimes called AMPylation 2 ) inactivates RhoGTPases, thereby inducing host cytoskeletal collapse. As such, Fic-mediated adenylylation allows the bacteria to evade phagocytosis by immune cells and/or breach the host’s protective cellular barriers 2,3 . We further demonstrated that the only human Fic domain-containing protein, HYPE/FicD, also has the ability to add AMP to RhoGTPases in vitro , but HYPE’s physiological target remains to be identified 1 . We have since shown that other nucleotides, such as GTP, CTP, and UTP, can also be utilized for Fic-mediated modifications 4 . Most recently, another bacterial Fic protein implicated in golgi breakdown and disruption of host vesicular trafficking was shown to hydrolyze a CTP derivative, called CDP-choline, to transfer not the nucleotide moiety but rather the phospho-choline to RabGTPases 5 . Thus, the Fic domain confers both nucleotidyl transferase as well as phospho-choline transferase activity. The goal of the Mattoo lab is to explore the role of Fic proteins in regulating prokaryotic and eukaryotic signal transduction events.
Our initial findings on Fic-mediated adenylylation were well received by the scientific community, being featured in the “Editor’s Choice” section in Science Magazine, the “Research Highlights” section of Nature Reviews Molecular Cell Biology , the “Spotlight” section in Infection and Immunity , and receiving a 9.0 score by the Faculty of 1000, indicating the wide interest in this new field. With over 5000 family members, Fic proteins have been implicated in processes as diverse as bacterial pathogenesis, cell division, protein translation, eukaryotic cell signaling, and cellular trafficking. Our goal is to identify substrates targeted for modification in these biological processes. Interestingly, an antibody directed against the Fic domain is protective against bacterial infection 6,7 . Thus, Fic proteins also offer a new avenue for design of vaccines and disease therapeutics .
1. C. Worby and S. Mattoo et al ., 2009, Mol. Cell , v.34, p.93.
2. M. Yarbrough et al. , 2009, Science , v.323, p.269
3. B. Zekarias, S. Mattoo, et al , 2010, Infect. Immun. , v.78, p.1850
4. S. Mattoo et al. , 2011, J. Biol. Chem. , v.323, p.269
5. S. Mukherjee et al. , 2011, Nature , v.477, n.7362, p.103
6. R. S. Geertsema et al ., 2008, Vaccine , v.26, n.35, p.4506
7. R. S. Geertsema et al ., 2011, Vaccine , v.29, n.29-30, p.4805
B.S. in Biochemistry (High Honors), University of Maryland, College Park Mentors: Drs. John W. Kozarich and Bruce B. Jarvis
Ph.D. in Microbiology & Immunology, UCLA
Mentor: Dr. Jeff F. Miller
Post-Doc, UC-San Diego
Mentor: Dr. Jack E. Dixon