Time Scales of Conformational Gating in a Lipid-Binding Protein

Kaieda, Shuji; Halle, Bertil

doi:10.1021/acs.jpcb.5b03214

Cited by 7 publications

(3 citation statements)

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“…Snapshots showing their location are found in Figure 14. One of these water molecules is located within hydrogen-bond distance of FABP5 residue Gly A water molecule in this location has been observed in multiple iLBPs and is thought to be important in the folding mechanism of this class of proteins (Kaieda & Halle, 2015;Kim, Ramanathan, & Frieden, 1997;Likic et al, 2000;Ropson & Frieden, 1992). The second water molecule with a long residence time is located between β-G and β-H and near residue Arg 109, an important residue for forming hydrogen bonds with water molecules in the FABP5 crystal structure.…”

Section: Trapped Water Moleculesmentioning

confidence: 97%

Molecular dynamics simulations ofapoandholoforms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules

Hunter

Bakula

Bruce

2017

Journal of Biomolecular Structure and Dynamics

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Structural and dynamic properties from a series of 300 ns molecular dynamics, MD, simulations of two intracellular lipid binding proteins, iLBPs, (Fatty Acid Binding Protein 5, FABP5, and Cellular Retinoic Acid Binding Protein II, CRABP-II) in both the apo form and when bound with retinoic acid reveal a high degree of protein and ligand flexibility. The ratio of FABP5 to CRABP-II in a cell may determine whether it undergoes natural apoptosis or unrestricted cell growth in the presence of retinoic acid. As a result, FABP5 is a promising target for cancer therapy. The MD simulations presented here reveal distinct differences in the two proteins and provide insight into the binding mechanism. CRABP-II is a much larger, more flexible protein that closes upon ligand binding, where FABP5 transitions to an open state in the holo form. The traditional understanding obtained from crystal structures of the gap between two β-sheets of the β-barrel common to iLBPs and the α-helix cap that forms the portal to the binding pocket is insufficient for describing protein conformation (open vs. closed) or ligand entry and exit. When the high degree of mobility between multiple conformations of both the ligand and protein are examined via MD simulation, a new mode of ligand motion that improves understanding of binding dynamics is revealed.

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Section: Trapped Water Moleculesmentioning

confidence: 97%

Molecular dynamics simulations ofapoandholoforms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules

Hunter

Bakula

Bruce

2017

Journal of Biomolecular Structure and Dynamics

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“…S10 ). The larger atom distributions of liganded-like dFABP in the portal region may have resulted from the use of ambiguous restraints for the aliphatic tail of the endogenous unknown ligand, while the internal hydration of water molecules within this region of apo-dFABP may result in more compact atom distributions (31). As shown in the 5GGE liganded-like dFABP structure, crystallization might preserve the slow-moving (gap region β E- F ) and promiscuous binding (portal region α II) sites where diverse positions occur.…”

Section: Resultsmentioning

confidence: 99%

The ligand-mediated affinity of escort proteins determines the directionality of lipophilic cargo transport

Cheng

Huang

Lin

et al. 2018

Preprint

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Intracellular cargo transport is a highly dynamic process. In eukaryotic cells, the uptake and release of lipophilic ligands are executed by escort proteins. However, how these carriers control the directionality of cargo trafficking remains unclear. Here, we have elucidated the unliganded structure of an archetypal fatty acid-binding protein (FABP) and found that it possesses stronger binding affinity than its liganded counterpart towards empty nanodiscs. Titrating unliganded FABP and nanodiscs with long-chain fatty acids (LCFAs) rescued the broadening of FABP cross-peak intensities in HSQC spectra due to decreased protein-membrane interaction. Crystallographic studies revealed that the tails of bound LCFAs obstructed the charged interfaces of the FABP–nanodisc complexes. We conclude that the lipophilic ligands, by taking advantage of escort proteins with high conformational homogeneity and nanodiscs as the third interaction partner involved in this transport study, participate directly in the control of their own transportation in an irreversible, unidirectional fashion.

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“…The EMOR SLE theory was first developed for quadrupolar relaxation 10,11 and it has been extensively applied to water 2 H MRD studies of colloidal silica, 12 polymer gels, 13,14 cross-linked proteins, [15][16][17][18] and cells. 19 As compared to quadrupolar relaxation, which only involves single spins, dipolar relaxation is theoretically more challenging.…”

Section: Introductionmentioning

confidence: 99%

Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems

Chang

Halle

2016

The Journal of Chemical Physics

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On the theory of the proton dipolar-correlation effect as a method for investigation of segmental displacement in polymer melts The Journal of Chemical Physics 147, 074904 (2017); 10.1063/1.4998184 THE JOURNAL OF CHEMICAL PHYSICS 144, 084202 (2016) Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems In aqueous systems with immobilized macromolecules, including biological tissue, the longitudinal spin relaxation of water protons is primarily induced by exchange-mediated orientational randomization (EMOR) of intra-and intermolecular magnetic dipole-dipole couplings. We have embarked on a systematic program to develop, from the stochastic Liouville equation, a general and rigorous theory that can describe relaxation by the dipolar EMOR mechanism over the full range of exchange rates, dipole coupling strengths, and Larmor frequencies. Here, we present a general theoretical framework applicable to spin systems of arbitrary size with symmetric or asymmetric exchange. So far, the dipolar EMOR theory is only available for a two-spin system with symmetric exchange. Asymmetric exchange, when the spin system is fragmented by the exchange, introduces new and unexpected phenomena. Notably, the anisotropic dipole couplings of non-exchanging spins break the axial symmetry in spin Liouville space, thereby opening up new relaxation channels in the locally anisotropic sites, including longitudinal-transverse cross relaxation. Such cross-mode relaxation operates only at low fields; at higher fields it becomes nonsecular, leading to an unusual inverted relaxation dispersion that splits the extreme-narrowing regime into two sub-regimes. The general dipolar EMOR theory is illustrated here by a detailed analysis of the asymmetric two-spin case, for which we present relaxation dispersion profiles over a wide range of conditions as well as analytical results for integral relaxation rates and time-dependent spin modes in the zero-field and motional-narrowing regimes. The general theoretical framework presented here will enable a quantitative analysis of frequency-dependent water-proton longitudinal relaxation in model systems with immobilized macromolecules and, ultimately, will provide a rigorous link between relaxation-based magnetic resonance image contrast and molecular parameters. C 2016 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license

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Time Scales of Conformational Gating in a Lipid-Binding Protein

Cited by 7 publications

References 50 publications

Molecular dynamics simulations ofapoandholoforms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules

Molecular dynamics simulations ofapoandholoforms of fatty acid binding protein 5 and cellular retinoic acid binding protein II reveal highly mobile protein, retinoic acid ligand, and water molecules

The ligand-mediated affinity of escort proteins determines the directionality of lipophilic cargo transport

Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems

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