Carla Mattos

Full Professor
111 Hurtig Hall
Tel: 617-373-6166
c.mattos@neu.edu

Chemical Biology, Biochemistry of Signaling Proteins, Structural Biology

Education:

Postdoctoral: Harvard University; Brandeis University
PhD: Massachusetts Institute of Technology

B.A.: Clark University

Research Interests

GTPases of the Ras Family; Protein Interactions; Protein X-ray Crystallography; Solvent Mapping of Protein Surfaces; Structure Based Ligand Discovery

Research in the Mattos Lab focuses on understanding the rules that govern the recognition, assembly and function of macromolecular complexes. It is clear that macromolecular interactions are central to the proper functioning, regulation and specificity of any cellular process, for example, signaling, transport, and replication. We are particularly interested in the protein-protein interactions that allow these assemblies to form in a specific manner. We are also interested in how small ligands are able to mediate or interfere with these interactions.

The biological system studied in this lab involves a group of closely related members of the Ras superfamily of GTPases. The protein-protein interactions mediating signal transduction pathways in which these GTPases are involved result in diverse and highly specific biological outcomes, including the control of cell proliferation, cell motility, transport of proteins across the nuclear membrane and many others. Ras and its family members normally have a disordered active site, which explains the intrinsically slow rate of GTP hydrolysis measured for these enzymes in solution. The active site is modulated by protein binding partners in both its regulation and in interaction with effector proteins which propagate signaling. In addition, our group has recently discovered an allosteric mechanism through which binding of ligand at a remote allosteric site orders the active site in Ras, suggesting a new mechanism for the intrinsic hydrolysis reaction. We are actively investigating this mechanism, the components of the allosteric switch and how it is impaired in a variety of mutants.

Figure 1. Active site of Ras GTPase ordered upon binding of ligand to the remote allosteric site. From Buhrman, Holzapfel, Fetics and Mattos, PNAS 107, 4931-4936 (2010).

The Mattos lab is also engaged in the study of protein binding sites and differences in properties of sites of protein ligand interactions versus binding sites for water molecules. We work on the development of methods to study solvents and their functional roles on the surfaces of proteins. The MSCS method is a powerful tool based on X-ray crystallography. It involves using organic solvents and small solutes as molecular probes to protein surfaces in order to both locate and characterize sites of protein-protein or protein-ligand interactions. In general, the method consists of growing crystals of the target protein in aqueous mother liquor and crosslinking the crystals with gluteraldehyde. This makes the crystals less likely to dissolve once transferred to organic solvent/water mixtures. Typically the soaking solutions contain at least 50% by volume of an organic solvent such as dimethylformamide, trifluoroethanol, isopropanol, cyclopentanol, etc. About ten crystal structures of the protein are obtained, each in a solvent condition, and the models are superimposed for analysis. Remarkably, the organic solvent molecules displace water molecules primarily at sites that evolved as binding sites. The superimposed structures therefore reveal clusters of organic solvents at hot-spots within protein binding pockets. Most recently we developed the program entitled Detection of Related Solvent Positions (DroP) for the analysis of crystallographic water molecules and other solvents across several structures of the same or related proteins. It is also the primary analysis tool for MSCS data sets. The method takes into account space group symmetries, raking of water conservation among a set of structures, and renumbering of water molecules according to the rank so that a water molecule at a given protein binding site has the same number in all structures. Use of DRoP allows for a more straight-forward correlation between structure and function of solvents on protein surfaces.

Figure 2. Results of MSCS analysis of RNAse A. From Dechene, Wink, Smith, Swartz and Mattos, Proteins: Structure, Function and Bioinformatics 76, 861-881 (2009).

The tools used in our laboratory include protein crystallography, computational biophysics, molecular biology and biochemistry. In addition we collaborate with cell biologists to correlate our structural biology work with results obtained in the context of the cellular environment.

Selectred Publications

Holzapfel, G., Buhrman, G. and Mattos, C., Shift in equilibrium between on and off states of the allosteric switch in Ras-GppNHp is affected by bulk solvent composition, submitted (2012).

Prior, I. A., Lewis, P. D., Mattos, C., A comprehensive survey of Ras mutations in cancer, Cancer Research, in press (2012).

Buhrman, G., O’Connor, C., Zerbe, B., Kearney, B. M., Napoleon, R., Kovrigina, E. A., Vajda, S., Kozakov, D., Kovrigin, E. L., and Mattos, C., Analysis of binding site hot spots on the surface of Ras GTPase, Journal of Molecular Biology, 413, 773-789 (2011).

Burhman, G., Kumar, S., Cirit, M., Haugh, J. M., and Mattos, C. Allosteric modulation of Ras-GTP is linked to signal transduction through Raf kinase. Journal of Biological Chemistry, 286, 3323-3331 (2011).

Buhrman, G., Holzapfel, G., Fetics, S. and Mattos, C., Allosteric modulation of Ras positions Q61 for a direct role in catalysis, PNAS, 107, 4931-4936 (2010).

Dechene, M., Wink, G., Smith, M., Swartz, P. and Mattos, C., Multiple Solvent Crystal Structures of Ribonuclease A: An Assessment of the Method, Proteins: Structure, Function and Bioinformatics, 76, 861-881 (2009).

Buhrman, G., Wink, G. and Mattos, C., Transformation efficiency of RasQ61 mutants linked to structural features of the switch regions in the presence of Raf, Structure, 15, 1618-1629 (2007).

Mattos, C., Bellamacina, C., Peisach, E., Pereira, A., Vitkup, D., Petsko, G.A. and Ringe, D., Multiple Solvent Crystal Structures: Probing Binding Sites, Plasticity and Hydration, Journal of Molecular Biology, 357, 1471-1482 (2006).

Buhrman, G., Parker, B., Sohn, J., Rudolph, J. and Mattos, C., Structural mechanism of oxidative regulation of the phosphatase Cdc25B via an intramolecular disulfide bond, Biochemistry, 44, 5307-5316 (2005).

Nicely, N., Kosak, J., de Serrano, V., and Mattos, C., Crystal Structures of Ral-GppNHp and Ral-GDP Reveal Two Binding Sites That Are Also Present in Ras and Rap, Structure, 12, 2025-2036 (2004).

Buhrman, G., de Serrano, V., and Mattos, C., Organic Solvents Order the Dynamic Switch II in Ras Crystals, Structure 11, 747-751 (2003).