Membrane proteins play an essential role in controlling the movement of material and information in and out of the cell, in determining the flow and use of energy, as well as in triggering the initiation of numerous signaling pathways. To fulfill these roles, conformational and interaction dynamics exert a dominant influence on their functional behavior, for it is the interplay between structure and dynamics what ultimately defines their function. The Membrane Protein Structural Dynamics Consortium (MPSDC) is proposed as a highly interactive, tightly integrated and multidisciplinary effort focused on elucidating the relationship between structure, dynamics and function in a variety of membrane proteins. The MMPSD will be organized around multidisciplinary project teams formed by investigators from 14 institutions in five different countries. These teams will study major mechanistic questions associated with membrane protein function as it relates to two major areas: energy transduction in signaling (ion channels and receptors) and energy inter-conversion (transporters and pumps). Ultimately, our goal is to decode the general mechanistic principles that govern protein movement and its associated fluctuation dynamics by dissecting and analyzing the molecular and dynamical bases of these functions at an unprecedented and quantitative level, as well as exploiting this information to engineer altered and novel activities into membrane protein frameworks to rationally evolve new functions. To accomplish its goals, the MPSDC will develop in parallel a set of tools, concepts and reagents to: 1) Apply state of the art spectroscopic methods (Magnetic Resonance, Fluorescence, 2D-IR) to follow conformational changes and dynamics of the determined structures;2) Correlate dynamic measurements with high-resolution ensemble and single molecule functional measurements;and 3) Design and implement novel computational approaches to link static and dynamic data with function. Six core facilities will feed and interconnect with the individual projects in a highly interactive way. The cores will act as both, """"""""innovation incubators"""""""" and research support centers by providing service and expertise In these critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a variety of binders and other crystallization chaperones and other target binders, the development of common computational tools to interpret and integrate the wealth of experimental data, the generation of novel, highly specific synthetic toxins and the continuous discovery of novel targets through the use of metagenomics tools.

Public Health Relevance

The interplay between structure and dynamics what ultimately defines a biological system's functional mechanism. Knowledge of how these fundamental phenomena influence the way membrane proteins function will be required to understand both the complex web of signaling and energy transduction mechanisms required for normal cellular function and their pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54GM087519-05
Application #
8728264
Study Section
Special Emphasis Panel (ZGM1-CBB-3 (GL))
Program Officer
Chin, Jean
Project Start
2010-08-10
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$4,242,609
Indirect Cost
$872,638
Name
University of Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Mahinthichaichan, Paween; Morris, Dylan M; Wang, Yi et al. (2018) Selective Permeability of Carboxysome Shell Pores to Anionic Molecules. J Phys Chem B 122:9110-9118
Li, Jing; Ostmeyer, Jared; Cuello, Luis G et al. (2018) Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel. J Gen Physiol 150:1408-1420
Kerr, Daniel; Tietjen, Gregory T; Gong, Zhiliang et al. (2018) Sensitivity of peripheral membrane proteins to the membrane context: A case study of phosphatidylserine and the TIM proteins. Biochim Biophys Acta Biomembr 1860:2126-2133
Litvinov, Aleksei; Feintuch, Akiva; Un, Sun et al. (2018) Triple resonance EPR spectroscopy determines the Mn2+ coordination to ATP. J Magn Reson 294:143-152
Carrasquel-Ursulaez, Willy; Alvarez, Osvaldo; Bezanilla, Francisco et al. (2018) Determination of the Stoichiometry between ?- and ?1 Subunits of the BK Channel Using LRET. Biophys J 114:2493-2497
Kintzer, Alexander F; Green, Evan M; Dominik, Pawel K et al. (2018) Structural basis for activation of voltage sensor domains in an ion channel TPC1. Proc Natl Acad Sci U S A 115:E9095-E9104
Quick, Matthias; Abramyan, Ara M; Wiriyasermkul, Pattama et al. (2018) The LeuT-fold neurotransmitter:sodium symporter MhsT has two substrate sites. Proc Natl Acad Sci U S A 115:E7924-E7931
Nissen, Neel I; Anderson, Kristin R; Wang, Huaixing et al. (2018) Augmenting the antinociceptive effects of nicotinic acetylcholine receptor activity through lynx1 modulation. PLoS One 13:e0199643
Sun, Chang; Benlekbir, Samir; Venkatakrishnan, Padmaja et al. (2018) Structure of the alternative complex III in a supercomplex with cytochrome oxidase. Nature 557:123-126
Mahinthichaichan, Paween; Gennis, Robert B; Tajkhorshid, Emad (2018) Cytochrome aa3 Oxygen Reductase Utilizes the Tunnel Observed in the Crystal Structures To Deliver O2 for Catalysis. Biochemistry 57:2150-2161

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