Delta-Peptide Is the Carboxy-Terminal Cleavage Fragment of the Nonstructural Small Glycoprotein sGP of Ebola Virus

Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT1R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy-terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT1R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy-terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase ( P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase ( P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold ( P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts.

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Inhibition of Tau Polymerization by Its Carboxy-Terminal Caspase Cleavage Fragment†

Biochemistry ◽

10.1021/bi027348m ◽

2003 ◽

Vol 42 (27) ◽

pp. 8325-8331 ◽

Cited By ~ 85

Author(s):

R. W. Berry ◽

A. Abraha ◽

S. Lagalwar ◽

N. LaPointe ◽

T. C. Gamblin ◽

...

Keyword(s):

Caspase Cleavage ◽

Cleavage Fragment ◽

Carboxy Terminal ◽

Tau Polymerization

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Non-canonical proline-tyrosine interactions with multiple host proteins regulate Ebola virus infection

10.1101/2020.05.19.102954 ◽

2020 ◽

Author(s):

Jyoti Batra ◽

Manu Anantpadma ◽

Gabriel I. Small ◽

Olena Shtanko ◽

Mengru Zhang ◽

...

Keyword(s):

Rna Synthesis ◽

Ebola Virus ◽

Host Protein ◽

Affinity Tag ◽

Binding Studies ◽

Host Proteins ◽

Variable Capacity ◽

Competition Binding ◽

Hydrogen Deuterium ◽

Carboxy Terminal

AbstractThe Ebola virus VP30 protein interacts with the viral nucleoprotein and with host protein RBBP6 via PPxPxY motifs. In these interactions the largely alpha-helical carboxy-terminal domain of the EBOV VP30 engages with the motif such that the prolines adopt non-canonical orientations, as compared to other proline-rich motifs. Affinity tag-purification mass spectrometry identified additional PPxPxY-containing host proteins, including hnRNP L, hnRNPUL1 and PEG10, as VP30 interactors. Of these, hnRNP L and PEG10, like RBBP6, inhibit viral RNA synthesis and EBOV replication, whereas hnRNPUL1 enhances. Further, double knockdown studies support additive effects of RBBP6 and hnRNP L. Binding studies demonstrate variable capacity of PPxPxY motifs to bind VP30 and the extended motif PxPPPPxY is demonstrated to confer optimal binding and to inhibit RNA synthesis, with the fifth proline and the tyrosine being most critical. Competition binding and hydrogen-deuterium exchange studies demonstrate that each protein binds a similar interface on VP30 and impacts VP30 phosphorylation. VP30 therefore represents a novel proline recognition domain that allows multiple host proteins to target a single viral protein-protein interface to modulate viral transcription.

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Inhibition of Platelet Adhesion to Fibrin(ogen) in Flowing Whole Blood by Arg-Gly-Asp and Fibrinogen γ-Chain Carboxy Terminal Peptides

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646346 ◽

1992 ◽

Vol 68 (06) ◽

pp. 694-700 ◽

Cited By ~ 25

Author(s):

Roy R Hantgan ◽

Silvia C Endenburg ◽

I Cavero ◽

Gérard Marguerie ◽

André Uzan ◽

...

Keyword(s):

Platelet Aggregation ◽

Whole Blood ◽

Platelet Adhesion ◽

Integrin Receptor ◽

Shear Rates ◽

Perfusion Chamber ◽

Receptor Recognition ◽

Adhesive Interactions ◽

Coated Surfaces ◽

Carboxy Terminal

SummaryWe have employed synthetic peptides with sequences corresponding to the integrin receptor-recognition regions of fibrinogen as inhibitors of platelet aggregation and adhesion to fibrinogen-and fibrin-coated surfaces in flowing whole blood, using a rectangular perfusion chamber at wall shear rates of 300 s–1 and 1,300 s–1. D-RGDW caused substantial inhibition of platelet aggregation and adhesion to fibrinogen and fibrin at both shear rates, although it was least effective at blocking platelet adhesion to fibrin at 300 s–1. RGDS was a weaker inhibitor, and produced a biphasic dose-response curve; SDRG was inactive. HHLGGAK-QAGDV partially inhibited platelet aggregation and adhesion to fibrin(ogen) at both shear rates. These results support the identification of an RGD-specific receptor, most likely the platelet integrin glycoprotein IIb: III a, as the primary receptor responsible for platelet: fibrin(ogen) adhesive interactions under flow conditions, and indicate that platelet adhesion to surface bound fibrin(ogen) is stabilized by multivalent receptor-ligand contacts.

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The Ability of Fibrinogens, FI and FII, to Support ADP- Induced Platelet Aggregation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1665246 ◽

1983 ◽

Vol 50 (02) ◽

pp. 527-529 ◽

Cited By ~ 4

Author(s):

H M Phillips ◽

A Mansouri ◽

C A Perry

Keyword(s):

Platelet Aggregation ◽

Terminal Portion ◽

Hepes Buffer ◽

Carboxy Terminal

SummaryFibrinogen plays an integral part in ADP-induced platelet aggregation. Controversy exists in regard to the role of the carboxy termini of fibrinogen Aa chains in this reaction. We have attempted to clarify this problem in view of the availability of a highly purified FII fibrinogen fraction. Kabi fibrinogen or its purified fractions FI, FII and FIII-IV-V were added to washed platelets in the presence of Tyrode-HEPES buffer pH 7.4. Aggregation was initiated by the addition of calcium and ADP. These fibrinogen fractions equally promoted ADP-induced platelet aggregation. The major difference among these fractions is in their Aα chains. The FI fraction contains intact Aα chains while FII and FIH-IV-V fractions have one and two partially degraded Aα chains at the carboxy terminal portion respectively. We conclude that the carboxy terminal portion of the Aα chain does not play an important role in promoting ADP-induced platelet aggregation.

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Treatment of ebola and other infectious diseases: melatonin “goes viral”

Melatonin Research ◽

10.32794/mr11250047 ◽

2020 ◽

Vol 3 (1) ◽

pp. 43-57 ◽

Cited By ~ 21

Author(s):

Russel J Reiter ◽

Qiang Ma ◽

Ramaswamy Sharma

Keyword(s):

Mortality Rate ◽

Infectious Diseases ◽

Hemorrhagic Shock ◽

Safety Profile ◽

Ebola Virus ◽

Viral Infections ◽

Virus Disease ◽

Attractive Potential ◽

Potential Treatment

This review summarizes published reports on the utility of melatonin as a treatment for virus-mediated diseases. Of special note are the data related to the role of melatonin in influencing Ebola virus disease. This infection and deadly condition has no effective treatment and the published works documenting the ability of melatonin to attenuate the severity of viral infections generally and Ebola infection specifically are considered. The capacity of melatonin to prevent one of the major complications of an Ebola infection, i.e., the hemorrhagic shock syndrome, which often contributes to the high mortality rate, is noteworthy. Considering the high safety profile of melatonin, the fact that it is easily produced, inexpensive and can be self-administered makes it an attractive potential treatment for Ebola virus pathology.

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