How transmembrane (TM) domains of membrane proteins transmit the signal across the cell membrane has long been a subject of keen interest in biology. There is a recent paradigm shift in the mechanism of activation for the cytokine receptor superfamily. The role of cytokine hormone binding to the extracellular domain is now recognized as an "inducer" of the conformational change of pre-dimerized TM domains that triggers subsequent intracellular responses. This is drastically different from its traditional role as an "organizer" whose sole function was to initiate the receptor TM dimer formation. Our long-term objective is to delineate the mechanisms and accompanying energetics of TM-induced signaling of various single-pass TM receptors during the inactive to active transition upon ligand binding. Our hypothesis is that the inactive off-state conformation is much more stable than the active on-state one, and the major role of ligand binding is to disrupt the pre-dimerized (energetically stable) TM-TM contact that locks-in the off-state structure, to direct the (energetically unstable) on-state structure. In this proposal, we will use human growth hormone receptor (hGHR) and human prolactin receptor (hPRLR) as prototypical model systems for homodimeric TM-induced activation. The objectives of this proposal are to determine the interfacial residues of hGHR and hPRLR TM dimers and to elucidate the conformational and energetic changes during the activation process by innovative, multidisciplinary combination of versatile computational and experimental approaches. The successful completion of this project will have a significant impact on the field, not only by elucidating the TM signaling mechanism and energetics, but also by providing the computational and experimental methods that can be used to characterize the biological activation process of other cytokine receptors and the plentitude of other single-pass TM receptors, which all have the critical importance to biology and thus, human health.

Public Health Relevance

How transmembrane domains of membrane proteins transmit the signal across the cell membrane has long been a subject of interest and challenge in biology. This project seeks to not only elucidate the transmembrane signaling mechanism and energetics, but also provide the computational and experimental methods that can be used to characterize the biological activation process of other cytokine receptors and the plentitude of other single-pass transmembrane receptors, which all have the critical importance to biology and thus, human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM092950-03
Application #
8299076
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Chin, Jean
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$279,770
Indirect Cost
$54,934
Name
University of Kansas Lawrence
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Krshnan, Logesvaran; Park, Soohyung; Im, Wonpil et al. (2016) A conserved αβ transmembrane interface forms the core of a compact T-cell receptor-CD3 structure within the membrane. Proc Natl Acad Sci U S A 113:E6649-E6658
Mori, Takaharu; Miyashita, Naoyuki; Im, Wonpil et al. (2016) Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms. Biochim Biophys Acta 1858:1635-51
Im, Wonpil; Liang, Jie; Olson, Arthur et al. (2016) Challenges in structural approaches to cell modeling. J Mol Biol 428:2943-64
Knoblich, Konstantin; Park, Soohyung; Lutfi, Mariam et al. (2015) Transmembrane Complexes of DAP12 Crystallized in Lipid Membranes Provide Insights into Control of Oligomerization in Immunoreceptor Assembly. Cell Rep 11:1184-92
Yao, Huili; Rui, Huan; Kumar, Ritesh et al. (2015) Concerted motions networking pores and distant ferroxidase centers enable bacterioferritin function and iron traffic. Biochemistry 54:1611-27
Li, Pai-Chi; Miyashita, Naoyuki; Im, Wonpil et al. (2014) Multidimensional umbrella sampling and replica-exchange molecular dynamics simulations for structure prediction of transmembrane helix dimers. J Comput Chem 35:300-8
Park, Soohyung; Im, Wonpil (2013) Two Dimensional Window Exchange Umbrella Sampling for Transmembrane Helix Assembly. J Chem Theory Comput 9:13-17
Lee, Hui Sun; Jo, Sunhwan; Lim, Hyun-Suk et al. (2012) Application of binding free energy calculations to prediction of binding modes and affinities of MDM2 and MDMX inhibitors. J Chem Inf Model 52:1821-32
Lee, Hui Sun; Im, Wonpil (2012) Identification of ligand templates using local structure alignment for structure-based drug design. J Chem Inf Model 52:2784-95
Rui, Huan; Rivera, Mario; Im, Wonpil (2012) Protein dynamics and ion traffic in bacterioferritin. Biochemistry 51:9900-10

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