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Repurposing Hsp104 to Antagonize Seminal Amyloid and Counter HIV Infection.
- Source :
-
Chemistry & Biology . Aug2015, Vol. 22 Issue 8, p1074-1086. 13p. - Publication Year :
- 2015
-
Abstract
- Summary Naturally occurring proteolytic fragments of prostatic acid phosphatase (PAP248-286 and PAP85-120) and semenogelins (SEM1 and SEM2) form amyloid fibrils in seminal fluid, which capture HIV virions and promote infection. For example, PAP248-286 fibrils, termed SEVI (semen-derived enhancer of viral infection), can potentiate HIV infection by several orders of magnitude. Here, we design three disruptive technologies to rapidly antagonize seminal amyloid by repurposing Hsp104, an amyloid-remodeling nanomachine from yeast. First, Hsp104 and an enhanced engineered variant, Hsp104 A503V , directly remodel SEVI and PAP85-120 fibrils into non-amyloid forms. Second, we elucidate catalytically inactive Hsp104 scaffolds that do not remodel amyloid structure, but cluster SEVI, PAP85-120, and SEM1(45–107) fibrils into larger assemblies. Third, we modify Hsp104 to interact with the chambered protease ClpP, which enables coupled remodeling and degradation to irreversibly clear SEVI and PAP85-120 fibrils. Each strategy diminished the ability of seminal amyloid to promote HIV infection, and could have therapeutic utility. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10745521
- Volume :
- 22
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- Chemistry & Biology
- Publication Type :
- Academic Journal
- Accession number :
- 108942594
- Full Text :
- https://doi.org/10.1016/j.chembiol.2015.07.007