To understand how signaling proteins function, it is crucial to know the timeordered sequence of events that lead to the signaling state. When the messenger is chemical, the time required to diffuse to and bind in the active site of a signaling protein is typically far longer than the timescale for protein conformational change [1]. For the structural determination of the kinetics of enzymatic reactions we will focus on small GTPases and their co-enzymes. Small GTPases are molecular switches that cycle between a GTP-bound active and a GDP-bound inactive form. The switch is catalyzed by Guanine nucleotide Exchange Factors (GEFs) and GTPase-Activating Proteins (GAPs), the latter catalyze the hydrolysis of GTP to GDP to deactivate the small GTPase. This system is of very high, general importance in cell biology with particular impact on disease processes, especially cancer, but also several infectious diseases. For proof-ofprinciple, we chose the Arl3-RP2 complex as GTPase-GAP pair [2]. The gene encoding for the GAP protein RP2 (Retinitis pigmentosa 2) is highly mutated in patients of X-linked Retinitis pigmentosa, with mutational hotspots in residues catalyzing the GAP reaction on Arl3. Retinitis pigmentosa refers to a heterogeneous group of inherited ocular diseases that result in a progressive retinal degeneration affecting 1 in 3,000?5,000 people.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Illinois Institute of Technology
United States
Zip Code
Korasick, David A; White, Tommi A; Chakravarthy, Srinivas et al. (2018) NAD+ promotes assembly of the active tetramer of aldehyde dehydrogenase 7A1. FEBS Lett 592:3229-3238
Kiss, Balázs; Lee, Eun-Jeong; Ma, Weikang et al. (2018) Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle. Proc Natl Acad Sci U S A 115:10369-10374
Huang, Wei; Peng, Yi; Kiselar, Janna et al. (2018) Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains. Nat Commun 9:3520
Ruszkowska, Agnieszka; Ruszkowski, Milosz; Dauter, Zbigniew et al. (2018) Structural insights into the RNA methyltransferase domain of METTL16. Sci Rep 8:5311
LaRochelle, Jonathan R; Fodor, Michelle; Vemulapalli, Vidyasiri et al. (2018) Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition. Nat Commun 9:4508
Ma, Weikang; Gong, Henry; Kiss, Balázs et al. (2018) Thick-Filament Extensibility in Intact Skeletal Muscle. Biophys J 115:1580-1588
Ma, Weikang; Gong, Henry; Irving, Thomas (2018) Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle. Int J Mol Sci 19:
Malaby, Andrew W; Das, Sanchaita; Chakravarthy, Srinivas et al. (2018) Structural Dynamics Control Allosteric Activation of Cytohesin Family Arf GTPase Exchange Factors. Structure 26:106-117.e6
Zhou, Bing-Rui; Jiang, Jiansheng; Ghirlando, Rodolfo et al. (2018) Revisit of Reconstituted 30-nm Nucleosome Arrays Reveals an Ensemble of Dynamic Structures. J Mol Biol 430:3093-3110
Yuan, Chen-Ching; Kazmierczak, Katarzyna; Liang, Jingsheng et al. (2018) Sarcomeric perturbations of myosin motors lead to dilated cardiomyopathy in genetically modified MYL2 mice. Proc Natl Acad Sci U S A 115:E2338-E2347

Showing the most recent 10 out of 143 publications