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Alignment of Alzheimer's Disease Amyloid-? Peptide and Herpes Simplex Virus-1 pUL15 C-Terminal Nuclease Domain.

ABSTRACT: Background:The cause of Alzheimer's disease (AD) is poorly understood. Neurotropic microbes, particularly herpesviruses, might set off chronic neuroinflammation. Amyloid-? (A?) has antimicrobial properties and could represent a brain defense against infection. Objective:We searched for protein sequence alignment between herpes simplex virus type I (HSV-1) HSV-2, and A?. Methods:Protein data bank (pdb) structures for A?, HSV-1, and HSV-2 were searched on the RCSB Protein Data Bank. The protein structures were superimposed and aligned on PYMOL v 2.3.4. Results:For HSV-1 and A?, amino acid residues ser549 - his569 of HSV-1 aligned closely with residues asp7 - asn27 of A?. For HSV-2 and A?, amino acid residues of HSV-2 aligned less closely than those of HSV-1 with residues of A?. Conclusion:Conjugating and binding to the same alpha helix in the HSV-1 protease, A? could be marking HSV-1 for attack by the immune system, providing a rapid inherited immune response to a destructive neurotropic virus that would otherwise require the more time-consuming involvement of T-cells, B-cells, and the adaptive immune system. But older people do not respond to viral infections as well as younger individuals. When HSV-1 infection advances in an old person, more and more amyloid is produced, forming an adhesive web. As the brain tries to hold the pathologic process in check, neuroinflammation increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

SUBMITTER: Lehrer S

PROVIDER: S-EPMC7592838 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Alignment of Alzheimer's Disease Amyloid-β Peptide and Herpes Simplex Virus-1 pUL15 C-Terminal Nuclease Domain.

Lehrer Steven S Rheinstein Peter H PH

Journal of Alzheimer's disease reports 20200909 1

<h4>Background</h4>The cause of Alzheimer's disease (AD) is poorly understood. Neurotropic microbes, particularly herpesviruses, might set off chronic neuroinflammation. Amyloid-β (Aβ) has antimicrobial properties and could represent a brain defense against infection.<h4>Objective</h4>We searched for protein sequence alignment between herpes simplex virus type I (HSV-1) HSV-2, and Aβ.<h4>Methods</h4>Protein data bank (pdb) structures for Aβ, HSV-1, and HSV-2 were searched on the RCSB Protein Dat ...[more]

PMID: 33163898

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Project description:The cause of Alzheimer's disease (AD) is poorly understood. In 1991, the amyloid hypothesis postulated that ?-amyloid (A?) accumulation is a key element. It follows that clearing the brain of A? would be beneficial, which has not been the case. Therefore, A? is likely a result, not a cause, of AD and may be protective rather than harmful. The apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for AD. Klotho (KL), encoded by the KL gene, may be another AD-related protein. FGF21 is a circulating endocrine hormone, mainly secreted by the liver, mostly during fasting. FGF21 acts by binding to its receptor FGFR1 and co-receptor ?-klotho. FGF21 is neuroprotective and could delay onset of AD. In the present study, the KL protein structure was examined to determine whether it may interact with A?. Protein data bank (pdb) entries for klotho and A? were searched on the RCSB Protein Data Bank for ?-KL and AD amyloid ?-peptide. The protein structures were superimposed and aligned on PYMOL v2.3.4 with the super command, which super aligns two protein selections. To evaluate the conservation and alignment of the A? and KL genomes across species, BLAT, the Blast-Like Alignment Tool of the UCSC Genome Browser, was used. The amino acid residues phe76-val96 of KL aligned closely with residues asp7-asn27 of A?. Cross-species comparison of KL revealed a high degree of alignment and conservation in the chimp and 27 other primates; however, less alignment and conservation were observed in the mouse, dog and elephant, even less in the chicken, western clawed frog (Xenopus tropicalis), zebrafish and lamprey. The current finding of amino acid residues phe76-val96 of klotho aligning closely with residues asp7-asn27 of A? suggests that A? can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD. The problem arises with age. Older individuals do not heal or repair tissue damage as well as younger individuals. As neurodegeneration advances in an older individual, perhaps caused by neuroinflammation related to herpes simplex virus type 1, increasing amounts of amyloid are produced, forming an adhesive web, as the brain tries to hold the pathologic process in check. Meanwhile, the damage increases and spreads. Progressive neurodegeneration and cognitive decline are the outcome.

Project description:UnlabelledHerpesviruses are nuclear-replicating viruses that have successfully evolved to evade the immune system of humans, establishing lifelong infections. ICP27 from herpes simplex virus is a multifunctional regulatory protein that is functionally conserved in all known human herpesviruses. It has the potential to interact with an array of cellular proteins, as well as intronless viral RNAs. ICP27 plays an essential role in viral transcription, nuclear export of intronless RNAs, translation of viral transcripts, and virion host shutoff function. It has also been implicated in several signaling pathways and the prevention of apoptosis. Although much is known about its central role in viral replication and infection, very little is known about the structure and mechanistic properties of ICP27 and its homologs. We present the first crystal structure of ICP27 C-terminal domain at a resolution of 2.0 Å. The structure reveals the C-terminal half of ICP27 to have a novel fold consisting of α-helices and long loops, along with a unique CHCC-type of zinc-binding motif. The two termini of this domain extend from the central core and hint to possibilities of making interactions. ICP27 essential domain is capable of forming self-dimers as seen in the structure, which is confirmed by analytical ultracentrifugation study. Preliminary in vitro phosphorylation assays reveal that this domain may be regulated by cellular kinases.ImportanceICP27 is a key regulatory protein of the herpes simplex virus and has functional homologs in all known human herpesviruses. Understanding the structure of this protein is a step ahead in deciphering the mechanism by which the virus thrives. In this study, we present the first structure of the C-terminal domain of ICP27 and describe its novel features. We critically analyze the structure and compare our results to the information available form earlier studies. This structure can act as a guide in future experimental designs and can add to a better understanding of mechanism of ICP27, as well as that of its homologs.

Project description:Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily enters local sensory neuronal processes, traveling retrograde to the neuronal nucleus to enter latency. Upon reawakening newly synthesized viral particles travel anterograde back to the epithelial cells of the lip, causing the recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a cellular transmembrane glycoprotein and receptor for anterograde transport machinery that when proteolyzed produces A-beta, the major component of senile plaques. Here we focus on transport inside epithelial cells of newly synthesized virus during its transit to the cell surface. We hypothesize that HSV1 recruits cellular APP during transport. We explore this with quantitative immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal imaging. After synchronous infection most nascent VP26-GFP-labeled viral particles in the cytoplasm co-localize with APP (72.8+/-6.7%) and travel together with APP inside living cells (81.1+/-28.9%). This interaction has functional consequences: HSV1 infection decreases the average velocity of APP particles (from 1.1+/-0.2 to 0.3+/-0.1 µm/s) and results in APP mal-distribution in infected cells, while interplay with APP-particles increases the frequency (from 10% to 81% motile) and velocity (from 0.3+/-0.1 to 0.4+/-0.1 µm/s) of VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor, gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid interactions are preserved while the distribution and dynamics of dual-label particles differ from wild-type by both immuno-fluorescence and live imaging. Knock-down of APP with siRNA eliminates APP staining, confirming specificity. Our results indicate that most intracellular HSV1 particles undergo frequent dynamic interplay with APP in a manner that facilitates viral transport and interferes with normal APP transport and distribution. Such dynamic interactions between APP and HSV1 suggest a mechanistic basis for the observed clinical relationship between HSV1 seropositivity and risk of Alzheimer's disease.

Dataset Information

Alignment of Alzheimer's Disease Amyloid-? Peptide and Herpes Simplex Virus-1 pUL15 C-Terminal Nuclease Domain.

Publications

Alignment of Alzheimer's Disease Amyloid-β Peptide and Herpes Simplex Virus-1 pUL15 C-Terminal Nuclease Domain.

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