Postdoctoral: Harvard University; Brandeis University PhD: Massachusetts Institute of Technology B.A.: Clark University

Chemical Biology, Biochemistry of Signaling Proteins, Structural Biology

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.

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.

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.

Expression, Purification, and Crystallization of the K-Ras Q61L and D92Y mutations J Henao, J Parker, C Mattos The FASEB Journal 29 (1 Supplement), 893.10

A Superfamily Reunion: Conserved Water Analysis of Small GTPases Using the Crystallography Tool DRoP K Marcus, C Mattos The FASEB Journal 29 (1 Supplement), 893.13

Probing the Structure and Function of the Helix-5 Water-Mediated Network in H-Ras J Sanchez, K Marcus, C Mattos The FASEB Journal 29 (1 Supplement), 893.12

Probing the Ras-membrane Interaction from a Structural Biology Perspective J Parker, C Mattos The FASEB Journal 29 (1 Supplement), 893.23

Neutron Crystal Structure of Ras GTPase sets New Paradigm for GTP Hydrolysis R Knihtila, G Holzapfel, K Weiss, F Meilleur, C Mattos The FASEB Journal 29 (1 Supplement), 893.7

Crystallization and Structural Determination of NRas D Reid, C Mattos The FASEB Journal 29 (1 Supplement), LB202

Allosteric Control of Conformational States in Ras Regulate the Intrinsic Hydrolysis Reaction in the Complex with Raf C Johnson, S Fetics, K Davis, J Rodriguez, C Mattos The FASEB Journal 29 (1 Supplement), 893.15

Ras Isoforms Conformational Clustering and Community Networks Studies: Simulating Ras with Accelerated Molecular Dynamics H Guterres, B Ma, R Nussinov, C Mattos The FASEB Journal 29 (1 Supplement), LB203

Multiple Solvent Crystal Structures of phage P22 tailspike protein: An analysis of binding site hot spots and surface hydration P Donohue, M Smith, N Broeker, C Doering, C Mattos, S Barbirz The FASEB Journal 29 (1 Supplement), 895.12

Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD SK Fetics, H Guterres, BM Kearney, G Buhrman, B Ma, R Nussinov, ... Structure 23 (3), 505-516

The Ras-membrane Interface: Isoform-specific Differences in the Catalytic Domain JA Parker, C Mattos Molecular Cancer Research, molcanres. 0535.2014

DRoP: A Water Analysis Program Identifies Ras-GTP-Specific Pathway of Communication between Membrane-Interacting Regions and the Active Site BM Kearney, CW Johnson, DM Roberts, P Swartz, C Mattos Journal of molecular biology 426 (3), 611-629

‘Pathway drug cocktail’: targeting Ras signaling based on structural pathways R Nussinov, CJ Tsai, C Mattos Trends in molecular medicine 19 (11), 695-704

Introduction: promoting concept driven teaching strategies in biochemistry and molecular biology C Mattos, M Johnson, H White, D Sears, C Bailey, E Bell Biochemistry and Molecular Biology Education 41 (5), 287-288

The Allosteric Switch and Conformational States in Ras GTPase Affected by Small Molecules. CW Johnson, C Mattos Inhibitors of the Ras Superfamily G-proteins, 41

The Multiple Solvent Crystal Structures Method of P22TSP MD Smith, C Mattos, S Barbirz The FASEB Journal 27 (1_MeetingAbstracts), lb161

Study of the effect of Ca (OAc) 2 concentration on the state of the Allosteric Switch in Ras GTPase CW Johnson, K Davis, C Mattos The FASEB Journal 27 (1_MeetingAbstracts), 831.17

Study of Ras catalytic mechanism of intrinsic hydrolysis of GTP R Knihtila, G Holzapfel, C Mattos The FASEB Journal 27 (1_MeetingAbstracts), 831.10

Multiple Solvent Crystal Structures of Rap1a GTPase P Donohue, C Mattos The FASEB Journal 27 (1_MeetingAbstracts), 1031.22

Allosteric modulation of caspase 3 through mutagenesis J Walters, JL Schipper, P Swartz, C Mattos, AC Clark Bioscience reports 32 (4), 401-411