16 results on '"Edward C. Twomey"'
Search Results
2. Aboard the ISS: intersubunit signaling revealed in the p97 ATPase
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Edward C, Twomey
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Proteasome Endopeptidase Complex ,Protein Folding ,Adenosine Triphosphate ,Valosin Containing Protein ,Proteostasis ,Animals ,Humans ,Endoplasmic Reticulum-Associated Degradation ,Endoplasmic Reticulum ,Signal Transduction - Published
- 2021
3. Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes
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Edward C. Twomey, Alexander I. Sobolevsky, and Maria V. Yelshanskaya
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0301 basic medicine ,Physiology ,Protein subunit ,Reviews ,Glutamic Acid ,Context (language use) ,Review ,AMPA receptor ,Neurotransmission ,Synaptic Transmission ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Receptors, AMPA ,Ion channel ,Neurons ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Glutamate receptor ,Brain ,Membrane Proteins ,Cell biology ,Protein Transport ,030104 developmental biology ,nervous system ,Claudins ,Excitatory postsynaptic potential ,Ionotropic glutamate receptor ,030217 neurology & neurosurgery - Abstract
Twomey et al. examine recent structural and functional data that have provided insight into AMPA receptor modulation by TARPs., Fast excitatory neurotransmission is mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptor (AMPAR). AMPARs initiate depolarization of the postsynaptic neuron by allowing cations to enter through their ion channel pores in response to binding of the neurotransmitter glutamate. AMPAR function is dramatically affected by auxiliary subunits, which are regulatory proteins that form various complexes with AMPARs throughout the brain. The most well-studied auxiliary subunits are the transmembrane AMPAR regulatory proteins (TARPs), which alter the assembly, trafficking, localization, kinetics, and pharmacology of AMPARs. Recent structural and functional studies of TARPs and the TARP-fold germ cell-specific gene 1-like (GSG1L) subunit have provided important glimpses into how auxiliary subunits regulate the function of synaptic complexes. In this review, we put these recent structures in the context of new functional findings in order to gain insight into the determinants of AMPAR regulation by TARPs. We thus reveal why TARPs display a broad range of effects despite their conserved modular architecture.
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- 2019
4. Structural Mechanisms of Gating in Ionotropic Glutamate Receptors
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Edward C. Twomey and Alexander I. Sobolevsky
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0301 basic medicine ,Protein Conformation ,Chemistry ,Cryoelectron Microscopy ,Glutamate receptor ,Gating ,Neurotransmission ,Crystallography, X-Ray ,Ligands ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,Postsynaptic potential ,Perspective ,Biophysics ,Excitatory postsynaptic potential ,Humans ,Receptors, AMPA ,Signal transduction ,Ion Channel Gating ,Ion channel ,Ionotropic effect - Abstract
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the central nervous system. iGluRs open their ion channels in response to binding of the neurotransmitter glutamate, rapidly depolarize the postsynaptic neuronal membrane, and initiate signal transduction. Recent studies using X-ray crystallography and cryo-electron microscopy have determined full-length iGluR structures that (1) uncover the receptor architecture in an unliganded, resting state, (2) reveal conformational changes produced by ligands in order to activate iGluRs, open their ion channels, and conduct ions, and (3) show how activated, glutamate-bound iGluRs can adopt a nonconducting desensitized state. These new findings, combined with the results of previous structural and functional experiments, kinetic and molecular modeling, mutagenesis, and biochemical analyses, provide new views on the structural mechanisms of iGluR gating.
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- 2017
5. Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding
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Edward C. Twomey, Jarrod A. Marto, Thomas E. Wales, Nicholas O. Bodnar, Tom A. Rapoport, Scott B. Ficarro, John R. Engen, and Zhejian Ji
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Nucleocytoplasmic Transport Proteins ,Saccharomyces cerevisiae Proteins ,ATPase ,Protein domain ,Vesicular Transport Proteins ,Article ,Substrate Specificity ,Motor protein ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Ubiquitin ,Multienzyme Complexes ,Valosin Containing Protein ,Polyubiquitin ,Protein Unfolding ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,Cryoelectron Microscopy ,ATPase complex ,Ubiquitination ,Substrate (chemistry) ,Proteasome ,Biophysics ,Unfolded protein response ,biology.protein ,030217 neurology & neurosurgery - Abstract
Protein unfolding, one substrate at a time Ubiquitin marks proteins for degradation by the proteasome. However, many substrates cannot be directly degraded because they are well folded or are located in cell membranes or in multimeric complexes. These proteins are first unfolded by the Cdc48 adenosine triphosphatase (ATPase), which forms a hexameric assembly that pulls polypeptides through its central pore. Twomey et al. determined structures of Cdc48 at an initiation stage of substrate processing. Surprisingly, a ubiquitin molecule in the substrate-linked polyubiquitin chain could be unfolded simply by binding to the Cdc48 complex. A segment of the unfolded ubiquitin inserts into the ATPase ring and initiates substrate unfolding. This explains why Cdc48 can deal with a broad range of substrates—even ones that are folded. Cooney et al. report the cryo–electron microscopy structure of Cdc48 in complex with an authentic substrate. In contrast to previously reported Cdc48 structures, an asymmetric spiraling assembly wraps around the extended substrate polypeptide. Thus, Cdc48 uses a hand-over-hand mechanism of translocation, which supports a common mechanism for protein substrate unfolding for AAA+ ATPases. Science , this issue p. eaax1033 , p. 502
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- 2019
6. Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy
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Joachim Frank, Maria V. Yelshanskaya, Edward C. Twomey, Robert A. Grassucci, and Alexander I. Sobolevsky
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Models, Molecular ,0301 basic medicine ,AMPA receptor ,Gating ,Neurotransmission ,Synaptic Transmission ,Protein Structure, Secondary ,Article ,03 medical and health sciences ,Protein structure ,Animals ,Humans ,Receptors, AMPA ,Multidisciplinary ,Protein Stability ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Cryoelectron Microscopy ,Glutamate receptor ,Brain ,Rats ,Transport protein ,HEK293 Cells ,030104 developmental biology ,nervous system ,Biochemistry ,Excitatory postsynaptic potential ,Biophysics ,Calcium Channels ,Ionotropic effect - Abstract
Stargazin and the AMPA receptor AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to higher cognitive processes such as learning and memory. In the brain, AMPARs exist as protein-protein complexes with various auxiliary subunits that tightly control AMPAR trafficking, gating, and pharmacology. Disruption of these complexes is implicated in numerous psychiatric and neurodegenerative diseases. Twomey et al. used cryo-electron microscopy to solve the structure of an AMPAR complex with stargazin (STZ), the major representative of transmembrane AMPAR regulatory proteins. STZ controls AMPAR synaptic targeting, synaptic plasticity, compartment-specific activity, pharmacology, and gating. Science , this issue p. 83
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- 2016
7. Mechanism of calmodulin inactivation of the calcium-selective TRP channel TRPV6
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Luke L. McGoldrick, Edward C. Twomey, Appu K. Singh, and Alexander I. Sobolevsky
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0301 basic medicine ,TRPV6 ,Calmodulin ,Protein Conformation ,chemistry.chemical_element ,TRPV Cation Channels ,Plasma protein binding ,macromolecular substances ,Calcium ,Biochemistry ,03 medical and health sciences ,Transient receptor potential channel ,Animals ,Humans ,Ion channel ,Research Articles ,Multidisciplinary ,Binding Sites ,030102 biochemistry & molecular biology ,biology ,Chemistry ,Calcium channel ,Cryoelectron Microscopy ,SciAdv r-articles ,3. Good health ,Rats ,030104 developmental biology ,biology.protein ,Biophysics ,Calcium Channels ,Intracellular ,Research Article ,Protein Binding - Abstract
Cryo-EM structures of the epithelial calcium channel TRPV6-calmodulin complex reveal a mechanism of Ca2+-induced inactivation., Calcium (Ca2+) plays a major role in numerous physiological processes. Ca2+ homeostasis is tightly controlled by ion channels, the aberrant regulation of which results in various diseases including cancers. Calmodulin (CaM)–mediated Ca2+-induced inactivation is an ion channel regulatory mechanism that protects cells against the toxic effects of Ca2+ overload. We used cryo-electron microscopy to capture the epithelial calcium channel TRPV6 (transient receptor potential vanilloid subfamily member 6) inactivated by CaM. The TRPV6-CaM complex exhibits 1:1 stoichiometry; one TRPV6 tetramer binds both CaM lobes, which adopt a distinct head-to-tail arrangement. The CaM carboxyl-terminal lobe plugs the channel through a unique cation-π interaction by inserting the side chain of lysine K115 into a tetra-tryptophan cage at the pore’s intracellular entrance. We propose a mechanism of CaM-mediated Ca2+-induced inactivation that can be explored for therapeutic design.
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- 2018
8. Channel opening and gating mechanism in AMPA-subtype glutamate receptors
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Edward C. Twomey, Maria V. Yelshanskaya, Robert A. Grassucci, Joachim Frank, and Alexander I. Sobolevsky
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- 2018
9. Opening of the human epithelial calcium channel TRPV6
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Appu K. Singh, Luke L. McGoldrick, Robert A. Grassucci, Alexander I. Sobolevsky, Maria V. Yelshanskaya, Kei Saotome, and Edward C. Twomey
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0301 basic medicine ,Multidisciplinary ,TRPV6 ,Alanine ,Ion Transport ,Rotation ,Chemistry ,Protein Conformation ,Calcium channel ,Cryoelectron Microscopy ,TRPV Cation Channels ,Epithelial Cells ,Gating ,03 medical and health sciences ,Transient receptor potential channel ,Transmembrane domain ,030104 developmental biology ,Protein structure ,Biophysics ,Humans ,Calcium ,Calcium Channels ,Ion Channel Gating ,Ion transporter ,Ion channel - Abstract
Calcium-selective transient receptor potential vanilloid subfamily member 6 (TRPV6) channels play a critical role in calcium uptake in epithelial tissues. Altered TRPV6 expression is associated with a variety of human diseases, including cancers. TRPV6 channels are constitutively active and their open probability depends on the lipidic composition of the membrane in which they reside; it increases substantially in the presence of phosphatidylinositol 4,5-bisphosphate. Crystal structures of detergent-solubilized rat TRPV6 in the closed state have previously been solved. Corroborating electrophysiological results, these structures demonstrated that the Ca2+ selectivity of TRPV6 arises from a ring of aspartate side chains in the selectivity filter that binds Ca2+ tightly. However, how TRPV6 channels open and close their pores for ion permeation has remained unclear. Here we present cryo-electron microscopy structures of human TRPV6 in the open and closed states. The channel selectivity filter adopts similar conformations in both states, consistent with its explicit role in ion permeation. The iris-like channel opening is accompanied by an α-to-π-helical transition in the pore-lining transmembrane helix S6 at an alanine hinge just below the selectivity filter. As a result of this transition, the S6 helices bend and rotate, exposing different residues to the ion channel pore in the open and closed states. This gating mechanism, which defines the constitutive activity of TRPV6, is, to our knowledge, unique among tetrameric ion channels and provides structural insights for understanding their diverse roles in physiology and disease.
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- 2017
10. Mechanism of glutamate receptor block by acylpolyamines
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Edward C. Twomey, Maria V. Yelshanskaya, Alexander A. Vassilevski, and Alexander I. Sobolevsky
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Mechanism (engineering) ,Chemistry ,Block (telecommunications) ,Glutamate receptor ,Biophysics ,Toxicology - Published
- 2019
11. Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors
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Maria V. Yelshanskaya, Edward C. Twomey, Alexander A. Vassilevski, and Alexander I. Sobolevsky
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0301 basic medicine ,Spider Venoms ,AMPA receptor ,Neurotransmission ,Protein Structure, Secondary ,Article ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Channel blocker ,Receptors, AMPA ,Ion channel ,Chemistry ,General Neuroscience ,Glutamate receptor ,Spider toxin ,Protein Structure, Tertiary ,Rats ,Electrophysiology ,HEK293 Cells ,030104 developmental biology ,nervous system ,Excitatory postsynaptic potential ,Calcium ,Excitatory Amino Acid Antagonists ,Neuroscience ,030217 neurology & neurosurgery - Abstract
AMPA receptors mediate fast excitatory neurotransmission and are critical for central nervous system development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including an orb weaver spider toxin AgTx-636, a spider toxin analog NASPM and an adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.
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- 2018
12. Characterization of temperature-sensing and PIP2-regulation of TRPV1 ion channel at the C-terminal domain using NMR spectroscopy and Molecular Dynamics Simulations
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Kelly A. Raymond, Edward C. Twomey, and Yufeng Wei
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Chemistry ,TRPV1 ,Context (language use) ,Biochemistry ,TRPC1 ,Transmembrane domain ,Transient receptor potential channel ,Genetics ,Biophysics ,Signal transduction ,Receptor ,Molecular Biology ,Ion channel - Abstract
Transient receptor potential (TRP) channels are receptors of stimulating signals, such as temperature, taste, odor, and chemo- and mechano-stimuli. Temperature sensing TRP channels coincidently function as pain receptors, and are potential targets for substances of abuse, including alcohol and illicit drugs. TRP vanilloid type 1 (TRPV1) channel is activated by heat (>43 °C) and capsaicin under the tight regulation of membrane-associated second messenger, PIP 2 (phosphatidylinositol-4,5-bisphosphate), responds to noxious stimuli and inflammatory substances, and could potentially modulate effects of alcohol and drugs of abuse. Despite the crucial roles in mediating signal transductions at both peripheral and central nervous systems, TRP channels are poorly understood in the context of structures and mechanisms. In this letter, we describe our initial structural characterization of the TRPV1 C-terminal domain, the putative temperature sensing and PIP 2 -regulatory domain, using NMR spectroscopy and molecular dynamics simulations. Both experimental and computational models suggest the C-terminal domain is intrinsically unstructured at room temperature with and without lipid bicelles. Elevated temperature and PIP 2 -binding can induce substantial conformational changes and formation of considerable secondary structural components in the C-terminal domain, which could be transduced to the transmembrane domain to potentially sensitize the channel.
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- 2014
13. Structural Bases of Desensitization in AMPA Receptor-Auxiliary Subunit Complexes
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Joachim Frank, Robert A. Grassucci, Alexander I. Sobolevsky, Edward C. Twomey, and Maria V. Yelshanskaya
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Models, Molecular ,0301 basic medicine ,Protein subunit ,Gating ,AMPA receptor ,Spodoptera ,Biology ,Neurotransmission ,Article ,Mice ,03 medical and health sciences ,Sf9 Cells ,Animals ,Humans ,Receptors, AMPA ,Protein Structure, Quaternary ,musculoskeletal, neural, and ocular physiology ,General Neuroscience ,Cryoelectron Microscopy ,Post-Synaptic Density ,Transmembrane protein ,Rats ,Protein Subunits ,Protein Transport ,HEK293 Cells ,030104 developmental biology ,nervous system ,Claudins ,Excitatory postsynaptic potential ,Biophysics ,Calcium Channels ,Ion Channel Gating ,Postsynaptic density ,Neuroscience ,Protein Binding ,Ionotropic effect - Abstract
Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local two-fold rotational symmetry. Our structural and functional experiments suggest that AMPAR auxiliary subunits share a modular architecture and use a common transmembrane scaffold for distinct extracellular modules to differentially regulate AMPAR gating. By comparing the AMPAR-GSG1L complex structures, we map conformational changes accompanying AMPAR recovery from desensitization and reveal structural bases for regulation of synaptic transmission by auxiliary subunits.
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- 2017
14. High-definition NMR structure of PED/PEA-15 death effector domain reveals details of key polar side chain interactions
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Edward C. Twomey and Yufeng Wei
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Hydrogen bond ,Chemistry ,Biophysics ,Intracellular Signaling Peptides and Proteins ,Structure validation ,Cell Biology ,Phosphoproteins ,Biochemistry ,Protein–protein interaction ,Protein Structure, Tertiary ,Crystallography ,Protein structure ,Residual dipolar coupling ,Side chain ,Humans ,Death effector domain ,Apoptosis Regulatory Proteins ,Molecular Biology ,Nuclear Magnetic Resonance, Biomolecular ,Death domain - Abstract
Death effector domain (DED) proteins constitute a subfamily of the large death domain superfamily that is primarily involved in apoptosis pathways. DED structures have characteristic side chain–side chain interactions among polar residues on the protein surface, forming a network of hydrogen bonds and salt bridges. The polar interaction network is functionally important in promoting protein–protein interactions by maintaining optimal side chain orientations. We have refined the solution DED structure of the PED/PEA-15 protein, a representative member of DED subfamily, using traditional NMR restraints with the addition of residual dipolar coupling (RDC) restraints from two independent alignment media, and employed the explicit solvent refinement protocol. The newly refined DED structure of PED/PEA-15 possesses higher structural quality as indicated by WHAT IF Z-scores, with most significant improvement in the backbone conformation normality quality factor. This higher quality DED structure of PED/PEA-15 leads to the identification of a number of key polar side chain interactions, which are not typically observed in NMR protein structures. The elucidation of polar side chain interactions is a key step towards the understanding of protein–protein interactions involving the death domain superfamily. The NMR structures with extensive details of protein structural features are thereby termed high-definition (HD) NMR structures.
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- 2012
15. Profound conformational changes of PED/PEA-15 in ERK2 complex revealed by NMR backbone dynamics
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Dana F. Cordasco, Yufeng Wei, and Edward C. Twomey
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MAPK/ERK pathway ,Magnetic Resonance Spectroscopy ,Protein Conformation ,Molecular Sequence Data ,Biophysics ,Biology ,Biochemistry ,Analytical Chemistry ,medicine ,FADD ,Amino Acid Sequence ,Molecular Biology ,Transcription factor ,Mitogen-Activated Protein Kinase 1 ,Intracellular Signaling Peptides and Proteins ,Phosphoproteins ,Cytosol ,medicine.anatomical_structure ,Cytoplasm ,Mitogen-activated protein kinase ,biology.protein ,Death effector domain ,Apoptosis Regulatory Proteins ,Nucleus - Abstract
PED/PEA-15 is a small, non-catalytic, DED containing protein that is widely expressed in different tissues and highly conserved among mammals. PED/PEA-15 has been found to interact with several protein targets in various pathways, including FADD and procaspase-8 (apoptosis), ERK1/2 (cell cycle entry), and PLD1/2 (diabetes). In this research, we have studied the PED/PEA-15 in a complex with ERK2, a MAP kinase, using NMR spectroscopic techniques. MAP Kinase signaling pathways are involved in the regulation of many cellular functions, including cell proliferation, differentiation, apoptosis and survival. ERK1/2 are activated by a variety of external stimuli, including growth factors, hormones and neurotransmitters. Inactivated ERK2 is primarily found in the cytosol. Once the ERK/MAPK cascade is initiated, ERK2 is phosphorylated and stimulated, allowing it to redistribute in the cell nucleus and act as a transcription factor. Previous studies have shown that PED/PEA-15 complexes with ERK2 in the cytoplasm and prevents redistribution into the nucleus. Although the NMR structure and dynamics of PED/PEA-15 in the free form have been documented recently, no detailed structural and dynamic information for the ERK2-bound form is available. Here we report NMR chemical shift perturbation and backbone dynamic studies at the fast ps–ns timescale of PED/PEA-15, in its free form and in the complex with ERK2. These analyses characterize motions and conformational changes involved in ERK2 recognition and binding that orchestrate the reorganization of the DED and immobilization of the C-terminal tail. A new induced fit binding model for PED/PEA-15 is proposed.
- Published
- 2012
16. Substantial Conformational Change Mediated by Charge-Triad Residues of the Death Effector Domain in Protein-Protein Interactions
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Edward C. Twomey, Stephen D. Kozuch, Yufeng Wei, and Dana F. Cordasco
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Proteomics ,Models, Molecular ,Conformational change ,lcsh:Medicine ,Signal transduction ,ERK signaling cascade ,Biochemistry ,01 natural sciences ,Protein Structure, Secondary ,Nuclear magnetic resonance ,Mice ,Molecular cell biology ,Protein structure ,Macromolecular Structure Analysis ,Biomacromolecule-Ligand Interactions ,lcsh:Science ,Mitogen-Activated Protein Kinase 1 ,0303 health sciences ,Multidisciplinary ,Effector ,Signaling cascades ,Small molecule ,Death effector domain ,Structural Proteins ,Research Article ,Protein Structure ,Death Domain Receptor Signaling Adaptor Proteins ,Static Electricity ,Biophysics ,Biology ,010402 general chemistry ,Protein–protein interaction ,03 medical and health sciences ,Animals ,Protein Interaction Domains and Motifs ,Protein Interactions ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,Proteins--Conformation ,lcsh:R ,Proteins ,Computational Biology ,Hydrogen Bonding ,Phosphoproteins ,0104 chemical sciences ,Residual dipolar coupling ,Phosphoprotein ,lcsh:Q ,Cytology ,Apoptosis Regulatory Proteins - Abstract
Protein conformational changes are commonly associated with the formation of protein complexes. The non-catalytic death effector domains (DEDs) mediate protein-protein interactions in a variety of cellular processes, including apoptosis, proliferation and migration, and glucose metabolism. Here, using NMR residual dipolar coupling (RDC) data, we report a conformational change in the DED of the phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) protein in the complex with a mitogen-activated protein (MAP) kinase, extracellular regulated kinase 2 (ERK2), which is essential in regulating ERK2 cellular distribution and function in cell proliferation and migration. The most significant conformational change in PEA-15 happens at helices α2, α3, and α4, which also possess the highest flexibility among the six-helix bundle of the DED. This crucial conformational change is modulated by the D/E-RxDL charge-triad motif, one of the prominent structural features of DEDs, together with a number of other electrostatic and hydrogen bonding interactions on the protein surface. Charge-triad motif promotes the optimal orientation of key residues and expands the binding interface to accommodate protein-protein interactions. However, the charge-triad residues are not directly involved in the binding interface between PEA-15 and ERK2.
- Published
- 2013
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