title: Kinetic timing: a novel mechanism that improves the accuracy of GTPase timers in endosome fusion and other biological processes.
abstract: The GTPase superfamily contains a large number of proteins that function as molecular switches by binding and hydrolyzing GTP molecules. They are localized at various intracellular organelles and control diverse cellular processes. For many GTPases, the lifetime of the activated, GTP-bound state is believed to serve as a timer in determining the activation time of a biological event such as membrane fusion and signal transduction. However, such a timer is intrinsically stochastic due to thermal noise at the level of single GTPase molecules. Here, we describe a mathematical model that shows how a directional GTPase cycle, in a nonequilibrium steady-state driven by GTP hydrolysis, can significantly reduce the variance in the lifetime of an activated GTPase molecule and thereby increase the accuracy and efficiency of the timer. This mechanism, termed kinetic timing, articulates a clear function for the energy consumption in GTPase-controlled biological processes. It provides a rationale for why biological timers utilize a GTP hydrolysis cycle rather than a simple GTP binding-dissociation equilibrium, and why the GTP-bound state is a better timer than the GDP-bound state. It also explains the necessity for the existence of multiple GTP-bound intermediates identified by fluorescence spectroscopy and nuclear magnetic resonance studies.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 SL. Young Blvd., BMSB 853, Oklahoma City, OK 73104, USA. guangpu-li@ouhsc.edu
authors.forename: Guangpu
authors.initials: G
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Qian
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D011992:Endosomes / Q000378:metabolism*; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000737:chemistry* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008962:Models, Theoretical; D011487:Protein Conformation; D015398:Signal Transduction; D013997:Time Factors; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D020696:rab5 GTP-Binding Proteins