scholarly journals The Membrane Interaction of Alpha-Synuclein

2021 ◽  
Vol 15 ◽  
Author(s):  
Cencen Liu ◽  
Yunfei Zhao ◽  
Huan Xi ◽  
Jie Jiang ◽  
Yang Yu ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Functional Role ◽  
Physiological Function ◽  
Alpha Synuclein ◽  
Nerve Terminals ◽  
Membrane Interaction ◽  
Pathogenic Mechanisms ◽  
C Terminus ◽  
N Terminus ◽  
Presynaptic Protein

A presynaptic protein closely related to Parkinson's disease (PD), α-synuclein (α-Syn), has been studied extensively regarding its pathogenic mechanisms. As a physiological protein in presynapses, however, α-Syn's physiological function remains unclear. Its location in nerve terminals and effects on membrane fusion also imply its functional role in synaptic transmission, including its possible interaction with high-curvature membranes via its N-terminus and amorphous C-terminus. PD-related mutants that disrupt the membrane interaction (e.g., A30P and G51D) additionally suggest a relationship between α-Syn's pathogenic mechanisms and physiological roles through the membrane binding. Here, we summarize recent research on how α-Syn and its variants interact with membranes and influence synaptic transmission. We list several membrane-related connections between the protein's physiological function and the pathological mechanisms that stand to expand current understandings of α-Syn.

Retention of cleaved synaptosome-associated protein of 25 kDa (SNAP-25) in neuromuscular junctions: a new hypothesis to explain persistence of botulinum A poisoning

1999 ◽  
Vol 77 (9) ◽  
pp. 679-688 ◽  
Author(s):  
Dorota A Raciborska ◽  
Milton P Charlton
Keyword(s):  
Botulinum Toxin ◽  
Neuromuscular Junctions ◽  
Botulinum Toxin Type A ◽  
Botulinum Toxin Type ◽  
Slight Reduction ◽  
Nerve Terminals ◽  
C Terminus ◽  
N Terminus ◽  
Botulinum Neurotoxins ◽  
C And N

Botulinum neurotoxins can block neurotransmitter release for several months. The molecular mechanism of these toxins' action is known, but the persistence of neuromuscular paralysis that they cause is unexplained. At frog neuromuscular junctions, application of botulinum toxin type A caused paralysis and reduced the C-terminus immunoreactivity of SNAP-25, but not that of the remaining N-terminus fragment. Botulinum toxin type C caused paralysis and reduced syntaxin immunoreactivity without affecting that of SNAP-25. Co-application of botulinum A and C reduced syntaxin immunoreactivity, and that of both C and N termini of SNAP-25. Application of hydroxylamine to de-palmitoylate SNAP-25 resulted in a slight reduction of the immunoreactivity of SNAP-25 N terminus, while it had no effect on immunoreactivity of botulinum A cleaved SNAP-25. In contrast, application of hydroxylamine to nerve terminals where syntaxin had been cleaved by botulinum C caused a considerable reduction in SNAP-25 N-terminus immunoreactivity. Hence the retention of immunoreactive SNAP-25 at the neuromuscular junction depends on its interactions with syntaxin and plasma membrane. Persistence of cleaved SNAP-25 in nerve terminals may prevent insertion of new SNAP-25 molecules, thereby contributing to the longevity of botulinum A effects.Key words: SNAP receptor, neurotoxin, dystonia, botulism, torticollis.

Preparation and properties of three analogues of [5-leucine]enkephalin, substrates for enzyme conversion studies

1985 ◽  
Vol 50 (6) ◽  
pp. 1329-1334
Author(s):  
Jaroslav Vičar ◽  
Linda Servítová ◽  
Martin Flegel ◽  
Karel Hauzer ◽  
Tomislav Barth
Keyword(s):  
High Pressure ◽  
Liquid Chromatography ◽  
Guinea Pig ◽  
Ion Exchange Chromatography ◽  
Exchange Chromatography ◽  
Guinea Pig Ileum ◽  
Opioid Activity ◽  
C Terminus ◽  
N Terminus ◽  
Fragment Condensation

Analogues of [5-Leu]enkephalin, prolonged by methionine on the N-terminus or, by lysine or methionine on the C-terminus were prepared by fragment condensation, purified by ion exchange chromatography or high-pressure liquid chromatography. The substances were characterised by their opioid activity in a test on guinea-pig ileum in comparison with the activity of [5-Leu]enkephalin.

scholarly journals Neurons and Glia Interplay in α-Synucleinopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri
Keyword(s):  
Glial Cells ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Glial Function ◽  
Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

scholarly journals The Prion-Like Spreading of Alpha-Synuclein in Parkinson’s Disease: Update on Models and Hypotheses

2021 ◽  
Vol 22 (15) ◽  
pp. 8338
Author(s):  
Asad Jan ◽  
Nádia Pereira Gonçalves ◽  
Christian Bjerggaard Vaegter ◽  
Poul Henning Jensen ◽  
Nelson Ferreira
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Cellular Factors ◽  
Recent Developments ◽  
Novel Targets ◽  
Presynaptic Protein

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson’s disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention. Here, we discuss recent developments on the hypothesis regarding trans-synaptic propagation of α-syn pathology in the context of neuronal vulnerability and highlight the potential utility of novel experimental models of synucleinopathies.

scholarly journals Improved Antimicrobial Activities of Synthetic-Hybrid Bacteriocins Designed from Enterocin E50-52 and Pediocin PA-1

2014 ◽  
Vol 81 (5) ◽  
pp. 1661-1667 ◽  
Author(s):  
Santosh Kumar Tiwari ◽  
Katia Sutyak Noll ◽  
Veronica L. Cavera ◽  
Michael L. Chikindas
Keyword(s):  
Micrococcus Luteus ◽  
Electrical Potential ◽  
Gram Negative Bacteria ◽  
Additional Advantage ◽  
Gram Negative ◽  
Content Type ◽  
Intracellular Atp ◽  
Hybrid Peptides ◽  
C Terminus ◽  
N Terminus

ABSTRACTTwo hybrid bacteriocins, enterocin E50-52/pediocin PA-1 (EP) and pediocin PA-1/enterocin E50-52 (PE), were designed by combining the N terminus of enterocin E50-52 and the C terminus of pediocin PA-1 and by combining the C terminus of pediocin PA-1 and the N terminus of enterocin E50-52, respectively. Both hybrid bacteriocins showed reduced MICs compared to those of their natural counterparts. The MICs of hybrid PE and EP were 64- and 32-fold lower, respectively, than the MIC of pediocin PA-1 and 8- and 4-fold lower, respectively, than the MIC of enterocin E50-52. In this study, the effect of hybrid as well as wild-type (WT) bacteriocins on the transmembrane electrical potential (ΔΨ) and their ability to induce the efflux of intracellular ATP were investigated. Enterocin E50-52, pediocin PA-1, and hybrid bacteriocin PE were able to dissipate ΔΨ, but EP was unable to deplete this component. Both hybrid bacteriocins caused a loss of the intracellular concentration of ATP. EP, however, caused a faster efflux than PE and enterocin E50-52. Enterocin E50-52 and hybrids PE and EP were active against the Gram-positive and Gram-negative bacteria tested, such asMicrococcus luteus,Salmonella entericaserovar Enteritidis 20E1090, andEscherichia coliO157:H7. The hybrid bacteriocins designed and described herein are antimicrobial peptides with MICs lower those of their natural counterparts. Both hybrid peptides induce the loss of intracellular ATP and are capable of inhibiting Gram-negative bacteria, and PE dissipates the electrical potential. In this study, the MIC of hybrid bacteriocin PE decreased 64-fold compared to the MIC of its natural peptide counterpart, pediocin PA-1. Inhibition of Gram-negative pathogens confers an additional advantage for the application of these peptides in therapeutics.

The SPI2-encoded SseA chaperone has discrete domains required for SseB stabilization and export, and binds within the C-terminus of SseB and SseD

Microbiology ◽  
2004 ◽  
Vol 150 (7) ◽  
pp. 2055-2068 ◽  
Author(s):  
Daniel V. Zurawski ◽  
Murry A. Stein
Keyword(s):  
Type Iii Secretion ◽  
Coiled Coil ◽  
Amphipathic Helix ◽  
Yeast Two Hybrid ◽  
C Terminus ◽  
N Terminus ◽  
Domain Mapping ◽  
Self Association ◽  
Discrete Domains ◽  
Two Hybrid

SseA, a key Salmonella virulence determinant, is a small, basic pI protein encoded within the Salmonella pathogenicity island 2 and serves as a type III secretion system chaperone for SseB and SseD. Both SseA partners are subunits of the surface-localized translocon module that delivers effectors into the host cell; SseB is predicted to compose the translocon sheath and SseD is a putative translocon pore subunit. In this study, SseA molecular interactions with its partners were characterized further. Yeast two-hybrid screens indicate that SseA binding requires a C-terminal domain within both partners. An additional central domain within SseD was found to influence binding. The SseA-binding region within SseB was found to encompass a predicted amphipathic helix of a type participating in coiled-coil interactions that are implicated in the assembly of translocon sheaths. Deletions that impinge upon this putative coiled-coiled domain prevent SseA binding, suggesting that SseA occupies a portion of the coiled-coil. SseA occupancy of this motif is envisioned to be sufficient to prevent premature SseB self-association inside bacteria. Domain mapping on the chaperone was also performed. A deletion of the SseA N-terminus, or site-directed mutations within this region, allowed stabilization of SseB, but its export was disrupted. Therefore, the N-terminus of SseA provides a function that is essential for SseB export, but dispensable for partner binding and stabilization.

scholarly journals Palmitoylation of Sindbis Virus TF Protein Regulates Its Plasma Membrane Localization and Subsequent Incorporation into Virions

2016 ◽  
Vol 91 (3) ◽  
Author(s):  
Jolene Ramsey ◽  
Emily C. Renzi ◽  
Randy J. Arnold ◽  
Jonathan C. Trinidad ◽  
Suchetana Mukhopadhyay
Keyword(s):  
Plasma Membrane ◽  
Sindbis Virus ◽  
Molecular Mechanisms ◽  
Wild Type Virus ◽  
Membrane Localization ◽  
Clear Understanding ◽  
Wild Type ◽  
Plasma Membrane Localization ◽  
C Terminus ◽  
N Terminus

ABSTRACT Palmitoylation is a reversible, posttranslational modification that helps target proteins to cellular membranes. The alphavirus small membrane proteins 6K and TF have been reported to be palmitoylated and to positively regulate budding. 6K and TF are isoforms that are identical in their N termini but unique in their C termini due to a −1 ribosomal frameshift during translation. In this study, we used cysteine (Cys) mutants to test differential palmitoylation of the Sindbis virus 6K and TF proteins. We modularly mutated the five Cys residues in the identical N termini of 6K and TF, the four additional Cys residues in TF's unique C terminus, or all nine Cys residues in TF. Using these mutants, we determined that TF palmitoylation occurs primarily in the N terminus. In contrast, 6K is not palmitoylated, even on these shared residues. In the C-terminal Cys mutant, TF protein levels increase both in the cell and in the released virion compared to the wild type. In viruses with the N-terminal Cys residues mutated, TF is much less efficiently localized to the plasma membrane, and it is not incorporated into the virion. The three Cys mutants have minor defects in cell culture growth but a high incidence of abnormal particle morphologies compared to the wild-type virus as determined by transmission electron microscopy. We propose a model where the C terminus of TF modulates the palmitoylation of TF at the N terminus, and palmitoylated TF is preferentially trafficked to the plasma membrane for virus budding. IMPORTANCE Alphaviruses are a reemerging viral cause of arthritogenic disease. Recently, the small 6K and TF proteins of alphaviruses were shown to contribute to virulence in vivo. Nevertheless, a clear understanding of the molecular mechanisms by which either protein acts to promote virus infection is missing. The TF protein is a component of budded virions, and optimal levels of TF correlate positively with wild-type-like particle morphology. In this study, we show that the palmitoylation of TF regulates its localization to the plasma membrane, which is the site of alphavirus budding. Mutants in which TF is not palmitoylated display drastically reduced plasma membrane localization, which effectively prevents TF from participating in budding or being incorporated into virus particles. Investigation of the regulation of TF will aid current efforts in the alphavirus field searching for approaches to mitigate alphaviral disease in humans.

scholarly journals Clusters of Charged Residues at the C Terminus of MotA and N Terminus of MotB Are Important for Function of the Escherichia coli Flagellar Motor

2008 ◽  
Vol 190 (15) ◽  
pp. 5517-5521 ◽  
Author(s):  
Edan R. Hosking ◽  
Michael D. Manson
Keyword(s):  
Escherichia Coli ◽  
Flagellar Motor ◽  
Protein Levels ◽  
Partner Protein ◽  
C Terminus ◽  
N Terminus ◽  
Charged Residues ◽  
Positively Charged ◽  
Terminal Cluster

ABSTRACT MotA contains a conserved C-terminal cluster of negatively charged residues, and MotB contains a conserved N-terminal cluster of positively charged residues. Charge-altering mutations affecting these residues impair motility but do not diminish Mot protein levels. The motility defects are reversed by second-site mutations targeting the same or partner protein.

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