My research focuses on understanding the regulation of the low molecular weight GTP-bindign proteins on a molecular level using biophysical and biochemical approaches. The deregulation of these proteins is the hallmark of many human illnesses including cancer and many infectious disases. More specifically, my laboratory is studying the protein-protein and protein-phospholipid interactions involved in the signaling of Ras and Rho GTPases.

One area of research is the regulation of the Dbl family protein Trio. Trio regulates axonal guidance and neuronal outgrowth by activating RhoG/Rac and Rho. We have determined the crystal structure of the RhoG/Rac activator (DH/PH) domain of Trio and shown that it binds phospholipid only in the presence of RhoG. Currently, we are studying how RhoG recruits Trio to membranes. In parallel,we are investigating the interaction between Trio and the actin capping protein Filamin.

A second area of research concerns the regulation of the scaffolding protein ELMO. ELMO is an 85kDa protein that is part of the CrkII/DOCK180/Rac complex involved in phagocytosis and cell engulfment. Since ELMO is also an effector of RhoG, it may facilitate the crosstalk between RhoG and Rac signaling pathways, which is important for the reorganization of the actin cytoskeleton in phagocytosis. Work conducted in the laboratory focuses on determining the crystal structure of ELMO and how it is recruited to membranes.

Selected readings:

Hall B. E., Bar-Sagi D., Nassar N. "The Structural basis for the transition from Ras.GTP to Ras.GDP" PNAS 99, 12138-12142 (2002).

Hoffman GR, Nassar N, Cerione RA "Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI" Cell, 100, 345-56 (2000).

Nicolas Nassar, Gregory R. Hoffman, Danny Manor, Jon C. Clardy and Richard Cerione "Transition state complex for GTP hydrolysis by Cdc42: Comparisons of the high resolution structures for Cdc42 bound to the active and catalytically compromised forms of the Cdc42-GAP" Nat. Struct. Biol., 5, 1047- 1052 (1998).

Louis Renault, Nicolas Nassar, Ingrid Vetter, Michel Roth and Alfred Wittinghofer "RCC1, the regulator of Chromosome Condensation and guanine nucleotide-exchange factor for the GTP-binding protein Ran, reveals at 1.7 Å resolution a propeller-like structure". Nature 392, 97-101 (1998).

Gregory R. Hoffman, Nicolas Nassar, Robert E. Oswald and Richard A. Cerione "Fluoride Activation of the Rho-family GTP-binding Protein Cdc42Hs" J. Biol. Chem. 273, 4392-4399 (1998).

Christian Herrmann and Nicolas Nassar. "Ras and its effectors" Prog. Biophys. molec. Biol., 66, N°1, 1-41 (1996).

Alfred Wittinghofer and Nicolas Nassar. "How Ras-related proteins talk to their effectors" TIBS, 21, 488-491 (1996).

Nicolas Nassar, Gudrun Horn, Christian Herrmann, Christoph Block, Ralf Janknecht & Alfred Wittinghofer. "Ras/Rap effector specificity determined by charge" Nature Structural Biology, 3, 723-729 (1996).

Christoph Block, Ralf Janknecht, Christian Herrmann, Nicolas Nassar and Alfred Wittinghofer "Quantitative structure-activity analysis correlating Ras/Raf interaction in vitro to Raf activation in vivo" Nature Structural Biology, 3, 244-251 (1996).

Nicolas Nassar, Gudrun Horn, Christian Herrmann, Anna Scherer, Franck McCormick & Alfred Wittinghofer. "The 2.2Å crystal structure of the Ras-binding domain of the serine/threonine kinase c-Raf1 in complex with Rap1A and a GTP analogue". Nature, 375, 554 - 560 (1995).