Terminase Large Subunit Provides a New Drug Target for Herpesvirus Treatment

Yang, Linlin; Yang, Qiao; Wang, Mingshu; Jia, Renyong; Chen, Shun; Zhu, Dekang; Liu, Mafeng; Wu, Ying; Zhao, Xinxin; Zhang, Shaqiu; Liu, Yunya; Yu, Yanling; Zhang, Ling; Chen, Xiaoyue; Cheng, Anchun

doi:10.3390/v11030219

Cited by 17 publications

(14 citation statements)

References 130 publications

(183 reference statements)

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“…Hence the virally encoded ATPases that drive dsDNA encapsidation provide a unique window into how maximum mechanical force can be extracted from chemical hydrolysis of ATP. In addition to serving as model systems to investigate the biophysical challenges associated with DNA condensation and ATPase mechanochemistry, these motors are attractive targets for therapeutics that inhibit dsDNA virus proliferation since there is no direct counterpart in eukaryotic cells [15].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Biophysical Characterization of the dsDNA packaging motor from theLactococcus lactisbacteriophage asccphi28

Reyes-Aldrete

Dill

Bussetta

et al. 2020

Preprint

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Double-stranded DNA viruses package their genomes into pre-assembled protein procapsids. This process is driven by macromolecular motors that transiently assemble at a unique vertex of the procapsid and utilize homomeric ring ATPases to couple genome encapsidation to ATP hydrolysis. Here we describe biochemical and biophysical characterization of the packaging ATPase from Lactococcus lactis phage asccφ28. Size-exclusion chromatography, analytical ultracentrifugation, small angle x-ray scattering, and negative stain TEM indicate that the ~45 kDa protein formed a 443 kDa cylindrical assembly with a maximum dimension of ~155 Å and radius of gyration of ~54 Å. Together with the dimensions of the crystallographic asymmetric unit from preliminary X-ray diffraction experiments, these results indicate that gp11 forms a decameric D5-symmetric complex consisting of two pentameric rings related by 2-fold symmetry. Additional kinetic analysis shows that recombinantly expressed gp11 has ATPase activity comparable to that of functional ATPase rings assembled on procapsids in other genome packaging systems. Hence, gp11 forms rings in solution that likely reflect the fully assembled ATPases in active virus-bound motor complexes. Whereas ATPase functionality in other dsDNA phage packaging systems requires assembly on viral capsids, the ability to form functional rings in solution imparts gp11 with significant advantages for high resolution structural studies and rigorous biophysical/biochemical analysis.

show abstract

Section: Introductionmentioning

confidence: 99%

Biochemical and Biophysical Characterization of the dsDNA packaging motor from theLactococcus lactisbacteriophage asccphi28

Reyes-Aldrete

Dill

Bussetta

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Hence the virally encoded ATPases that drive dsDNA encapsidation provide a unique window into how maximum mechanical force can be extracted from the chemical hydrolysis of ATP. Despite the general ubiquity of these motors in nature, the manner in which they are coupled to genome encapsidation in dsDNA viruses is unique; hence, these motors are attractive targets for therapeutics that inhibit viral packaging machinery [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Biophysical Characterization of the dsDNA Packaging Motor from the Lactococcus lactis Bacteriophage Asccphi28

Reyes-Aldrete

Dill

Bussetta

et al. 2020

Viruses

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Double-stranded DNA viruses package their genomes into pre-assembled protein procapsids. This process is driven by macromolecular motors that transiently assemble at a unique vertex of the procapsid and utilize homomeric ring ATPases to couple genome encapsidation to ATP hydrolysis. Here, we describe the biochemical and biophysical characterization of the packaging ATPase from Lactococcus lactis phage asccφ28. Size-exclusion chromatography (SEC), analytical ultracentrifugation (AUC), small angle X-ray scattering (SAXS), and negative stain transmission electron microscopy (TEM) indicate that the ~45 kDa protein formed a 443 kDa cylindrical assembly with a maximum dimension of ~155 Å and radius of gyration of ~54 Å. Together with the dimensions of the crystallographic asymmetric unit from preliminary X-ray diffraction experiments, these results indicate that gp11 forms a decameric D5-symmetric complex consisting of two pentameric rings related by 2-fold symmetry. Additional kinetic analysis shows that recombinantly expressed gp11 has ATPase activity comparable to that of functional ATPase rings assembled on procapsids in other genome packaging systems. Hence, gp11 forms rings in solution that likely reflect the fully assembled ATPases in active virus-bound motor complexes. Whereas ATPase functionality in other double-stranded DNA (dsDNA) phage packaging systems requires assembly on viral capsids, the ability to form functional rings in solution imparts gp11 with significant advantages for high-resolution structural studies and rigorous biophysical/biochemical analysis.

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“…This aspect is analogous to what occurs with both phage T3, and all other studied doublestranded DNA phages. Each of the major herpesvirus proteins involved is homologous to the phage counterpart [12,[20][21][22][23][24]. For developing a hypothesis, this is a pivotal point because phage assembly generated particles are generally more accessible than those of eukaryotic virus counterparts.…”

Section: Foundation For An Explanation: Detailsmentioning

confidence: 99%

A Protein Assembly Hypothesis for Population-Specific Decrease in Dementia with Time

Serwer

Wright

2021

Biophysica

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A recent report in the journal, Neurology, documents age-normalized, nation-specific (e.g., United States and Western Europe), progressive decrease of dementia, beginning about 25 years ago. This observation has, thus far, not had explanation. We begin our proposed explanation with the following previous disease construct. (1) Some dementia is caused by innate immune over-response to infections. (2) The innate immune over-response occurs via excessive conversion of amyloid protein to α-sheet conformation. (3) This conversion evolved to inhibit invading microbes by binding microbe-associated α-sheet, e.g., in hyper-expanded capsid intermediates of some viruses. The rarity of human α-sheet makes this inhibition specific for microbial invaders. As foundation, here we observe directly, for the first time, extreme, sheet-like outer shell thinness in a hyper-expanded capsid of phage T3. Based on phage/herpesvirus homology, we propose the following. The above decrease in dementia is caused by varicella-zoster virus (VZV) vaccination, USFDA-approved about 25 years ago; VZV is a herpesvirus and causes chickenpox and shingles. In China and Japan, a cotemporaneous non-decrease is explained by lower anti-VZV vaccination. Co-assembly extension of α-sheet is relatively independent of amino acid sequence. Thus, we project that additional dementia is suppressible by vaccination against other viruses, including other herpesviruses.

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Terminase Large Subunit Provides a New Drug Target for Herpesvirus Treatment

Cited by 17 publications

References 130 publications

Biochemical and Biophysical Characterization of the dsDNA packaging motor from theLactococcus lactisbacteriophage asccphi28

Biochemical and Biophysical Characterization of the dsDNA packaging motor from theLactococcus lactisbacteriophage asccphi28

Biochemical and Biophysical Characterization of the dsDNA Packaging Motor from the Lactococcus lactis Bacteriophage Asccphi28

A Protein Assembly Hypothesis for Population-Specific Decrease in Dementia with Time

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