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An alternative N-terminal fold of the intestine-specific annexin A13a induces dimerization and regulates membrane-binding.
McCulloch KM, Yamakawa I, Shifrin DA, McConnell RE, Foegeding NJ, Singh PK, Mao S, Tyska MJ, Iverson TM
(2019) J Biol Chem 294: 3454-3463
MeSH Terms: Animals, Annexins, Cell Membrane, Epithelial Cells, Humans, Hydrogen-Ion Concentration, Intestinal Mucosa, Intestines, Liposomes, Mice, Models, Molecular, Organ Specificity, Protein Binding, Protein Conformation, alpha-Helical, Protein Multimerization, Protein Structure, Quaternary, Protein Transport
Show Abstract · Added April 1, 2019
Annexin proteins function as Ca-dependent regulators of membrane trafficking and repair that may also modulate membrane curvature. Here, using high-resolution confocal imaging, we report that the intestine-specific annexin A13 (ANX A13) localizes to the tips of intestinal microvilli and determined the crystal structure of the ANX A13a isoform to 2.6 Å resolution. The structure revealed that the N terminus exhibits an alternative fold that converts the first two helices and the associated helix-loop-helix motif into a continuous α-helix, as stabilized by a domain-swapped dimer. We also found that the dimer is present in solution and partially occludes the membrane-binding surfaces of annexin, suggesting that dimerization may function as a means for regulating membrane binding. Accordingly, as revealed by binding and cellular localization assays, ANX A13a variants that favor a monomeric state exhibited increased membrane association relative to variants that favor the dimeric form. Together, our findings support a mechanism for how the association of the ANX A13a isoform with the membrane is regulated.
© 2019 McCulloch et al.
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17 MeSH Terms
Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.
Kamp F, Scheidt HA, Winkler E, Basset G, Heinel H, Hutchison JM, LaPointe LM, Sanders CR, Steiner H, Huster D
(2018) ACS Chem Neurosci 9: 1702-1713
MeSH Terms: Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Bexarotene, Cholesterol, HEK293 Cells, Humans, Liposomes, Molecular Structure, Neuroprotective Agents, Phosphatidylcholines, Protein Conformation, alpha-Helical, Protein Domains, Receptor, Notch1, Static Electricity
Show Abstract · Added November 21, 2018
Bexarotene is a pleiotropic molecule that has been proposed as an amyloid-β (Aβ)-lowering drug for the treatment of Alzheimer's disease (AD). It acts by upregulation of an apolipoprotein E (apoE)-mediated Aβ clearance mechanism. However, whether bexarotene induces removal of Aβ plaques in mouse models of AD has been controversial. Here, we show by NMR and CD spectroscopy that bexarotene directly interacts with and stabilizes the transmembrane domain α-helix of the amyloid precursor protein (APP) in a region where cholesterol binds. This effect is not mediated by changes in membrane lipid packing, as bexarotene does not share with cholesterol the property of inducing phospholipid condensation. Bexarotene inhibited the intramembrane cleavage by γ-secretase of the APP C-terminal fragment C99 to release Aβ in cell-free assays of the reconstituted enzyme in liposomes, but not in cells, and only at very high micromolar concentrations. Surprisingly, in vitro, bexarotene also inhibited the cleavage of Notch1, another major γ-secretase substrate, demonstrating that its inhibition of γ-secretase is not substrate specific and not mediated by acting via the cholesterol binding site of C99. Our data suggest that bexarotene is a pleiotropic molecule that interfere with Aβ metabolism through multiple mechanisms.
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14 MeSH Terms
Peripheral myelin protein 22 alters membrane architecture.
Mittendorf KF, Marinko JT, Hampton CM, Ke Z, Hadziselimovic A, Schlebach JP, Law CL, Li J, Wright ER, Sanders CR, Ohi MD
(2017) Sci Adv 3: e1700220
MeSH Terms: Cell Membrane, Charcot-Marie-Tooth Disease, Cysteine, Humans, Lipid Bilayers, Lipids, Liposomes, Mutation, Myelin Proteins, Recombinant Proteins
Show Abstract · Added November 21, 2018
Peripheral myelin protein 22 (PMP22) is highly expressed in myelinating Schwann cells of the peripheral nervous system. genetic alterations cause the most common forms of Charcot-Marie-Tooth disease (CMTD), which is characterized by severe dysmyelination in the peripheral nerves. However, the functions of PMP22 in Schwann cell membranes remain unclear. We demonstrate that reconstitution of purified PMP22 into lipid vesicles results in the formation of compressed and cylindrically wrapped protein-lipid vesicles that share common organizational traits with compact myelin of peripheral nerves in vivo. The formation of these myelin-like assemblies depends on the lipid-to-PMP22 ratio, as well as on the PMP22 extracellular loops. Formation of the myelin-like assemblies is disrupted by a CMTD-causing mutation. This study provides both a biochemical assay for PMP22 function and evidence that PMP22 directly contributes to membrane organization in compact myelin.
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10 MeSH Terms
Gβγ directly modulates vesicle fusion by competing with synaptotagmin for binding to neuronal SNARE proteins embedded in membranes.
Zurawski Z, Page B, Chicka MC, Brindley RL, Wells CA, Preininger AM, Hyde K, Gilbert JA, Cruz-Rodriguez O, Currie KPM, Chapman ER, Alford S, Hamm HE
(2017) J Biol Chem 292: 12165-12177
MeSH Terms: Animals, Binding, Competitive, Calcium Signaling, Cattle, Cell Line, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Humans, Lipid Bilayers, Liposomes, Membrane Fusion, Models, Molecular, Mutation, Nerve Tissue Proteins, Peptide Fragments, Protein Conformation, Protein Interaction Domains and Motifs, Protein Multimerization, Rats, Recombinant Fusion Proteins, Recombinant Proteins, Synaptosomal-Associated Protein 25, Synaptotagmin I, Syntaxin 1
Show Abstract · Added July 12, 2017
G-coupled G protein-coupled receptors can inhibit neurotransmitter release at synapses via multiple mechanisms. In addition to Gβγ-mediated modulation of voltage-gated calcium channels (VGCC), inhibition can also be mediated through the direct interaction of Gβγ subunits with the soluble -ethylmaleimide attachment protein receptor (SNARE) complex of the vesicle fusion apparatus. Binding studies with soluble SNARE complexes have shown that Gβγ binds to both ternary SNARE complexes, t-SNARE heterodimers, and monomeric SNAREs, competing with synaptotagmin 1(syt1) for binding sites on t-SNARE. However, in secretory cells, Gβγ, SNAREs, and synaptotagmin interact in the lipid environment of a vesicle at the plasma membrane. To approximate this environment, we show that fluorescently labeled Gβγ interacts specifically with lipid-embedded t-SNAREs consisting of full-length syntaxin 1 and SNAP-25B at the membrane, as measured by fluorescence polarization. Fluorescently labeled syt1 undergoes competition with Gβγ for SNARE-binding sites in lipid environments. Mutant Gβγ subunits that were previously shown to be more efficacious at inhibiting Ca-triggered exocytotic release than wild-type Gβγ were also shown to bind SNAREs at a higher affinity than wild type in a lipid environment. These mutant Gβγ subunits were unable to inhibit VGCC currents. Specific peptides corresponding to regions on Gβ and Gγ shown to be important for the interaction disrupt the interaction in a concentration-dependent manner. In fusion assays using full-length t- and v-SNAREs embedded in liposomes, Gβγ inhibited Ca/synaptotagmin-dependent fusion. Together, these studies demonstrate the importance of these regions for the Gβγ-SNARE interaction and show that the target of Gβγ, downstream of VGCC, is the membrane-embedded SNARE complex.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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24 MeSH Terms
Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein.
Mercredi PY, Bucca N, Loeliger B, Gaines CR, Mehta M, Bhargava P, Tedbury PR, Charlier L, Floquet N, Muriaux D, Favard C, Sanders CR, Freed EO, Marchant J, Summers MF
(2016) J Mol Biol 428: 1637-55
MeSH Terms: Cell Membrane, HIV-1, Lipids, Liposomes, Magnetic Resonance Spectroscopy, Membrane Microdomains, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylserines, Protein Binding, Protein Structure, Tertiary, gag Gene Products, Human Immunodeficiency Virus
Show Abstract · Added November 21, 2018
Assembly of HIV-1 particles is initiated by the trafficking of viral Gag polyproteins from the cytoplasm to the plasma membrane, where they co-localize and bud to form immature particles. Membrane targeting is mediated by the N-terminally myristoylated matrix (MA) domain of Gag and is dependent on the plasma membrane marker phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Recent studies revealed that PI(4,5)P2 molecules containing truncated acyl chains [tr-PI(4,5)P2] are capable of binding MA in an "extended lipid" conformation and promoting myristoyl exposure. Here we report that tr-PI(4,5)P2 molecules also readily bind to non-membrane proteins, including HIV-1 capsid, which prompted us to re-examine MA-PI(4,5)P2 interactions using native lipids and membrane mimetic liposomes and bicelles. Liposome binding trends observed using a recently developed NMR approach paralleled results of flotation assays, although the affinities measured under the equilibrium conditions of NMR experiments were significantly higher. Native PI(4,5)P2 enhanced MA binding to liposomes designed to mimic non-raft-like regions of the membrane, suggesting the possibility that binding of the protein to disordered domains may precede Gag association with, or nucleation of, rafts. Studies with bicelles revealed a subset of surface and myr-associated MA residues that are sensitive to native PI(4,5)P2, but cleft residues that interact with the 2'-acyl chains of tr-PI(4,5)P2 molecules in aqueous solution were insensitive to native PI(4,5)P2 in bicelles. Our findings call to question extended-lipid MA:membrane binding models, and instead support a model put forward from coarse-grained simulations indicating that binding is mediated predominantly by dynamic, electrostatic interactions between conserved basic residues of MA and multiple PI(4,5)P2 and phosphatidylserine molecules.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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MeSH Terms
Topologically Diverse Human Membrane Proteins Partition to Liquid-Disordered Domains in Phase-Separated Lipid Vesicles.
Schlebach JP, Barrett PJ, Day CA, Kim JH, Kenworthy AK, Sanders CR
(2016) Biochemistry 55: 985-8
MeSH Terms: Amyloid beta-Protein Precursor, Caveolin 3, Cholesterol, Fluorescent Dyes, Humans, Hydrophobic and Hydrophilic Interactions, Membrane Microdomains, Microscopy, Confocal, Microscopy, Fluorescence, Models, Molecular, Myelin Proteins, Peptide Fragments, Phosphatidylcholines, Phosphatidylethanolamines, Protein Conformation, Protein Interaction Domains and Motifs, Recombinant Proteins, Rhodamines, Sphingomyelins, Unilamellar Liposomes
Show Abstract · Added February 12, 2016
The integration of membrane proteins into "lipid raft" membrane domains influences many biochemical processes. The intrinsic structural properties of membrane proteins are thought to mediate their partitioning between membrane domains. However, whether membrane topology influences the targeting of proteins to rafts remains unclear. To address this question, we examined the domain preference of three putative raft-associated membrane proteins with widely different topologies: human caveolin-3, C99 (the 99 residue C-terminal domain of the amyloid precursor protein), and peripheral myelin protein 22. We find that each of these proteins are excluded from the ordered domains of giant unilamellar vesicles containing coexisting liquid-ordered and liquid-disordered phases. Thus, the intrinsic structural properties of these three topologically distinct disease-linked proteins are insufficient to confer affinity for synthetic raft-like domains.
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20 MeSH Terms
The Tubulation Activity of a Fission Yeast F-BAR Protein Is Dispensable for Its Function in Cytokinesis.
McDonald NA, Takizawa Y, Feoktistova A, Xu P, Ohi MD, Vander Kooi CW, Gould KL
(2016) Cell Rep 14: 534-546
MeSH Terms: Animals, COS Cells, Chlorocebus aethiops, Crystallography, X-Ray, Cytokinesis, Cytoskeletal Proteins, Dimerization, Liposomes, Microscopy, Electron, Protein Structure, Tertiary, Recombinant Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added February 4, 2016
F-BAR proteins link cellular membranes to the actin cytoskeleton in many biological processes. Here we investigated the function of the Schizosaccharomyces pombe Imp2 F-BAR domain in cytokinesis and find that it is critical for Imp2's role in contractile ring constriction and disassembly. To understand mechanistically how the F-BAR domain functions, we determined its structure, elucidated how it interacts with membranes, and identified an interaction between dimers that allows helical oligomerization and membrane tubulation. Using mutations that block either membrane binding or tubulation, we find that membrane binding is required for Imp2's cytokinetic function but that oligomerization and tubulation, activities often deemed central to F-BAR protein function, are dispensable. Accordingly, F-BARs that do not have the capacity to tubulate membranes functionally substitute for the Imp2 F-BAR, establishing that its major role is as a cell-cycle-regulated bridge between the membrane and Imp2 protein partners, rather than as a driver of membrane curvature.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Characterization of Cytokinetic F-BARs and Other Membrane-Binding Proteins.
McDonald NA, Gould KL
(2016) Methods Mol Biol 1369: 181-9
MeSH Terms: Cytokinesis, Liposomes, Membrane Proteins, Microscopy, Fluorescence, Molecular Imaging, Protein Binding, Protein Interaction Domains and Motifs
Show Abstract · Added February 4, 2016
Multiple membrane-binding proteins are key players in cytokinesis in yeast and other organisms. In vivo techniques for analyzing protein-membrane interactions are currently limited. In vitro assays allow characterization of the biochemical properties of these proteins to build a mechanistic understanding of protein-membrane interactions during cytokinesis. Here, we describe two in vitro assays to characterize FCH-Bin/Amphyphysin/RVS (F-BAR) domains and other protein's interactions with membranes: liposome co-pelleting and giant unilamellar vesicle fluorescent binding.
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7 MeSH Terms
Lipid Domains. Preface.
Kenworthy AK
(2015) Curr Top Membr 75: xiii-xvii
MeSH Terms: Animals, Humans, Membrane Microdomains, Unilamellar Liposomes
Added February 12, 2016
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4 MeSH Terms
Particle-based technologies for osteoarthritis detection and therapy.
Kavanaugh TE, Werfel TA, Cho H, Hasty KA, Duvall CL
(2016) Drug Deliv Transl Res 6: 132-47
MeSH Terms: Animals, Cell-Derived Microparticles, Delayed-Action Preparations, Dendrimers, Drug Delivery Systems, Humans, Liposomes, Micelles, Nanoparticles, Osteoarthritis
Show Abstract · Added March 14, 2018
Osteoarthritis (OA) is a disease characterized by degradation of joints with the development of painful osteophytes in the surrounding tissues. Currently, there are a limited number of treatments for this disease, and many of these only provide temporary, palliative relief. In this review, we discuss particle-based drug delivery systems that can provide targeted and sustained delivery of imaging and therapeutic agents to OA-affected sites. We focus on technologies such as polymeric micelles and nano-/microparticles, liposomes, and dendrimers for their potential treatment and/or diagnosis of OA. Several promising studies are highlighted, motivating the continued development of delivery technologies to improve treatments for OA.
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10 MeSH Terms