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Dodecyl-β-melibioside Detergent Micelles as a Medium for Membrane Proteins.
Hutchison JM, Lu Z, Li GC, Travis B, Mittal R, Deatherage CL, Sanders CR
(2017) Biochemistry 56: 5481-5484
MeSH Terms: Amyloid beta-Protein Precursor, Detergents, Diacylglycerol Kinase, Disaccharides, Dynamic Light Scattering, Enzyme Stability, Escherichia coli Proteins, Glucosides, Glycolipids, Hot Temperature, Humans, Micelles, Myelin Proteins, Nuclear Magnetic Resonance, Biomolecular, Particle Size, Peptide Fragments, Protein Interaction Domains and Motifs, Protein Stability, Receptor, Notch1
Show Abstract · Added November 21, 2018
There remains a need for new non-ionic detergents that are suitable for use in biochemical and biophysical studies of membrane proteins. Here we explore the properties of n-dodecyl-β-melibioside (β-DDMB) micelles as a medium for membrane proteins. Melibiose is d-galactose-α(1→6)-d-glucose. Light scattering showed the β-DDMB micelle to be roughly 30 kDa smaller than micelles formed by the commonly used n-dodecyl-β-maltoside (β-DDM). β-DDMB stabilized diacylglycerol kinase (DAGK) against thermal inactivation. Moreover, activity assays conducted using aliquots of DAGK purified into β-DDMB yielded activities that were 40% higher than those of DAGK purified into β-DDM. β-DDMB yielded similar or better TROSY-HSQC NMR spectra for two single-pass membrane proteins and the tetraspan membrane protein peripheral myelin protein 22. β-DDMB appears be a useful addition to the toolbox of non-ionic detergents available for membrane protein research.
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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
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
Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22.
Schlebach JP, Narayan M, Alford C, Mittendorf KF, Carter BD, Li J, Sanders CR
(2015) J Am Chem Soc 137: 8758-68
MeSH Terms: Amino Acid Sequence, Animals, Charcot-Marie-Tooth Disease, Dogs, Humans, Madin Darby Canine Kidney Cells, Metals, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Myelin Proteins, Peripheral Nervous System Diseases, Protein Conformation, Protein Folding, Protein Stability, Protein Transport, Thermodynamics
Show Abstract · Added February 20, 2016
Despite broad biochemical relevance, our understanding of the physiochemical reactions that limit the assembly and cellular trafficking of integral membrane proteins remains superficial. In this work, we report the first experimental assessment of the relationship between the conformational stability of a eukaryotic membrane protein and the degree to which it is retained by cellular quality control in the secretory pathway. We quantitatively assessed both the conformational equilibrium and cellular trafficking of 12 variants of the α-helical membrane protein peripheral myelin protein 22 (PMP22), the intracellular misfolding of which is known to cause peripheral neuropathies associated with Charcot-Marie-Tooth disease (CMT). We show that the extent to which these mutations influence the energetics of Zn(II)-mediated PMP22 folding is proportional to the observed reduction in cellular trafficking efficiency. Strikingly, quantitative analyses also reveal that the reduction of motor nerve conduction velocities in affected patients is proportional to the extent of the mutagenic destabilization. This finding provides compelling evidence that the effects of these mutations on the energetics of PMP22 folding lie at the heart of the molecular basis of CMT. These findings highlight conformational stability as a key factor governing membrane protein biogenesis and suggest novel therapeutic strategies for CMT.
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Of mothers and myelin: Aberrant myelination phenotypes in mouse model of Angelman syndrome are dependent on maternal and dietary influences.
Grier MD, Carson RP, Lagrange AH
(2015) Behav Brain Res 291: 260-267
MeSH Terms: Angelman Syndrome, Animals, Cerebral Cortex, Diet, High-Fat, Disease Models, Animal, Female, Heterozygote, Male, Maternal Nutritional Physiological Phenomena, Mice, Inbred C57BL, Mice, Knockout, Myelin Proteins, Phenotype, Receptors, Glucocorticoid, Sciatic Nerve, Spinal Cord, Ubiquitin-Protein Ligases
Show Abstract · Added March 14, 2018
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by a number of neurological problems, including developmental delay, movement disorders, and epilepsy. AS results from the loss of UBE3A (an imprinted gene) expressed from the maternal chromosome in neurons. Given the ubiquitous expression of Ube3a and the devastating nature of AS, the role of environmental and maternal effects has been largely ignored. Severe ataxia, anxiety-like behaviors and learning deficits are well-documented in patients and AS mice. More recently, clinical imaging studies of AS patients suggest myelination may be delayed or reduced. Utilizing a mouse model of AS, we found disrupted expression of cortical myelin proteins, the magnitude of which is influenced by maternal status, in that the aberrant myelination in the AS pups of AS affected mothers were more pronounced than those seen in AS pups raised by unaffected (Ube3a (m+/p-)) Carrier mothers. Furthermore, feeding the breeding mothers a higher fat (11% vs 5%) diet normalizes these myelin defects. These effects are not limited to myelin proteins. Since AS mice have abnormal stress responses, including altered glucocorticoid receptor (GR) expression, we measured GR expression in pups from Carrier and affected AS mothers. AS pups had higher GR expression than their WT littermates. However, we also found an effect of maternal status, with reduced GR levels in pups from affected mothers compared to genotypically identical pups raised by unaffected Carrier mothers. Taken together, our findings suggest that the phenotypes observed in AS mice may be modulated by factors independent of Ube3a genotype.
Published by Elsevier B.V.
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17 MeSH Terms
Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases.
Dortch RD, Dethrage LM, Gore JC, Smith SA, Li J
(2014) Neurology 83: 1545-53
MeSH Terms: Adult, Charcot-Marie-Tooth Disease, Cohort Studies, Disability Evaluation, Disabled Persons, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Myelin Proteins, Sciatic Neuropathy, Statistics as Topic, Young Adult
Show Abstract · Added October 15, 2014
OBJECTIVE - The objectives of this study were (1) to develop a novel magnetization transfer ratio (MTR) MRI assay of the proximal sciatic nerve (SN), which is inaccessible via current tools for assessing peripheral nerves, and (2) to evaluate the resulting MTR values as a potential biomarker of myelin content changes in patients with Charcot-Marie-Tooth (CMT) diseases.
METHODS - MTR was measured in the SN of patients with CMT type 1A (CMT1A, n = 10), CMT type 2A (CMT2A, n = 3), hereditary neuropathy with liability to pressure palsies (n = 3), and healthy controls (n = 21). Additional patients without a genetically confirmed subtype (n = 4), but whose family histories and electrophysiologic tests were consistent with CMT, were also included. The relationship between MTR and clinical neuropathy scores was assessed, and the interscan and inter-rater reliability of MTR was estimated.
RESULTS - Mean volumetric MTR values were significantly decreased in the SN of patients with CMT1A (33.8 ± 3.3 percent units) and CMT2A (31.5 ± 1.9 percent units) relative to controls (37.2 ± 2.3 percent units). A significant relationship between MTR and disability scores was also detected (p = 0.01 for genetically confirmed patients only, p = 0.04 for all patients). From interscan and inter-rater reliability analyses, proximal nerve MTR values were repeatable at the slicewise and mean volumetric levels.
CONCLUSIONS - MTR measurements may be a viable biomarker of proximal nerve pathology in patients with CMT.
© 2014 American Academy of Neurology.
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14 MeSH Terms
The homology model of PMP22 suggests mutations resulting in peripheral neuropathy disrupt transmembrane helix packing.
Mittendorf KF, Kroncke BM, Meiler J, Sanders CR
(2014) Biochemistry 53: 6139-41
MeSH Terms: Amino Acid Sequence, Claudins, Crystallography, X-Ray, Models, Molecular, Molecular Sequence Data, Mutation, Myelin Proteins, Peripheral Nervous System Diseases, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Homology, Amino Acid
Show Abstract · Added January 20, 2015
Peripheral myelin protein 22 (PMP22) is a tetraspan membrane protein strongly expressed in myelinating Schwann cells of the peripheral nervous system. Myriad missense mutations in PMP22 result in varying degrees of peripheral neuropathy. We used Rosetta 3.5 to generate a homology model of PMP22 based on the recently published crystal structure of claudin-15. The model suggests that several mutations known to result in neuropathy act by disrupting transmembrane helix packing interactions. Our model also supports suggestions from previous studies that the first transmembrane helix is not tightly associated with the rest of the helical bundle.
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12 MeSH Terms
Influence of Pathogenic Mutations on the Energetics of Translocon-Mediated Bilayer Integration of Transmembrane Helices.
Schlebach JP, Sanders CR
(2015) J Membr Biol 248: 371-81
MeSH Terms: Amino Acid Sequence, Animals, Cattle, Conserved Sequence, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, KCNQ1 Potassium Channel, Lipid Bilayers, Mutation, Mutation, Missense, Myelin Proteins, Protein Structure, Secondary, Protein Transport, Receptors, Vasopressin, Rhodopsin, Thermodynamics
Show Abstract · Added November 21, 2018
Aberrant protein folding and assembly contribute to a number of diseases, and efforts to rationalize how pathogenic mutations cause this phenomenon represent an important imperative in biochemical research. However, for α-helical membrane proteins, this task is complicated by the fact that membrane proteins require intricate machinery to achieve structural and functional maturity under cellular conditions. In this work, we utilized the ΔG predictor algorithm ( www.dgpred.cbr.su.se ) to survey 470 known pathogenic mutations occurring in five misfolding-prone α-helical membrane proteins for their predicted effects on the translocon-mediated membrane integration of transmembrane helices, a critical step in biosynthesis and folding of nascent membrane proteins. The results suggest that about 10 % of these mutations are likely to have adverse effects on the topogenesis of nascent membrane proteins. These results suggest that the misfolding of a modest but nonetheless significant subset of pathogenic variants may begin at the translocon. Potential implications for therapeutic design and personalized medicine are discussed.
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The Nogo receptor NgR1 mediates infection by mammalian reovirus.
Konopka-Anstadt JL, Mainou BA, Sutherland DM, Sekine Y, Strittmatter SM, Dermody TS
(2014) Cell Host Microbe 15: 681-91
MeSH Terms: Animals, CHO Cells, Capsid Proteins, Cell Adhesion Molecules, Cell Membrane, Cricetulus, GPI-Linked Proteins, Host-Pathogen Interactions, Humans, Mice, Mutant Strains, Myelin Proteins, Neuraminidase, Neurons, Nogo Receptor 1, Receptors, Cell Surface, Reoviridae, Reoviridae Infections, Virion
Show Abstract · Added January 21, 2015
Neurotropic viruses, including mammalian reovirus, must disseminate from an initial site of replication to the central nervous system (CNS), often binding multiple receptors to facilitate systemic spread. Reovirus engages junctional adhesion molecule A (JAM-A) to disseminate hematogenously. However, JAM-A is dispensable for reovirus replication in the CNS. We demonstrate that reovirus binds Nogo receptor NgR1, a leucine-rich repeat protein expressed in the CNS, to infect neurons. Expression of NgR1 confers reovirus binding and infection of nonsusceptible cells. Incubating reovirus virions with soluble NgR1 neutralizes infectivity. Blocking NgR1 on transfected cells or primary cortical neurons abrogates reovirus infection. Concordantly, reovirus infection is ablated in primary cortical neurons derived from NgR1 null mice. Reovirus virions bind to soluble JAM-A and NgR1, while infectious disassembly intermediates (ISVPs) bind only to JAM-A. These results suggest that reovirus uses different capsid components to bind distinct cell-surface molecules, engaging independent receptors to facilitate spread and tropism.
Copyright © 2014 Elsevier Inc. All rights reserved.
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18 MeSH Terms
Abnormal junctions and permeability of myelin in PMP22-deficient nerves.
Guo J, Wang L, Zhang Y, Wu J, Arpag S, Hu B, Imhof BA, Tian X, Carter BD, Suter U, Li J
(2014) Ann Neurol 75: 255-65
MeSH Terms: Action Potentials, Age Factors, Animals, Arthrogryposis, Axons, Disease Models, Animal, Gene Expression Regulation, HEK293 Cells, Hereditary Sensory and Motor Neuropathy, Humans, Junctional Adhesion Molecules, Mice, Mice, Transgenic, Mutation, Myelin Proteins, Myelin Sheath, Neural Conduction, Peripheral Nerves, Potassium, Tight Junction Proteins, Tight Junctions
Show Abstract · Added March 17, 2014
OBJECTIVE - The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability.
METHODS - Utilizing Pmp22(+) (/) (-) mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches.
RESULTS - We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain-containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP.
INTERPRETATION - Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.
© 2014 American Neurological Association.
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21 MeSH Terms