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1.
Nucleic Acids Res ; 50(19): 11109-11127, 2022 10 28.
Article in English | MEDLINE | ID: mdl-36200825

ABSTRACT

Mobile genetic elements control their life cycles by the expression of a master repressor, whose function must be disabled to allow the spread of these elements in nature. Here, we describe an unprecedented repression-derepression mechanism involved in the transfer of Staphylococcus aureus pathogenicity islands (SaPIs). Contrary to the classical phage and SaPI repressors, which are dimers, the SaPI1 repressor StlSaPI1 presents a unique tetrameric conformation never seen before. Importantly, not just one but two tetramers are required for SaPI1 repression, which increases the novelty of the system. To derepress SaPI1, the phage-encoded protein Sri binds to and induces a conformational change in the DNA binding domains of StlSaPI1, preventing the binding of the repressor to its cognate StlSaPI1 sites. Finally, our findings demonstrate that this system is not exclusive to SaPI1 but widespread in nature. Overall, our results characterize a novel repression-induction system involved in the transfer of MGE-encoded virulence factors in nature.


Subject(s)
Genomic Islands , Staphylococcus Phages , Genomic Islands/genetics , Staphylococcus Phages/genetics , Staphylococcus aureus/genetics
2.
J Biol Chem ; 289(41): 28707-18, 2014 Oct 10.
Article in English | MEDLINE | ID: mdl-25164817

ABSTRACT

The endosomal sorting complexes required for transport (ESCRTs) function in a variety of membrane remodeling processes including multivesicular body sorting, abscission during cytokinesis, budding of enveloped viruses, and repair of the plasma membrane. Vps4 ATPase activity modulates ESCRT function and is itself modulated by its cofactor Vta1 and its substrate ESCRT-III. The carboxyl-terminal Vta1/SBP-1/Lip5 (VSL) domain of Vta1 binds to the Vps4 ß-domain to promote Vps4 oligomerization-dependent ATP hydrolysis. Additionally, the Vps4 stimulatory element (VSE) of Vta1 contributes to enhancing Vps4 oligomer ATP hydrolysis. The VSE is also required for Vta1-dependent stimulation of Vps4 by ESCRT-III subunits. However, the manner by which the Vta1 VSE contributes to Vps4 activation is unknown. Existing structural data were used to generate a model of the Vta1 VSE in complex with Vps4. This model implicated residues within the small ATPase associated with various activities (AAA) domain, specifically α-helices 7 and 9, as relevant contact sites. Rational generation of Vps4 mutants defective for VSE-mediated stimulation, as well as intergenic compensatory mutations, support the validity of this model. These findings have uncovered the Vps4 surface responsible for coordinating ESCRT-III-stimulated Vta1 input during ESCRT function and identified a novel mechanism of Vps4 stimulation.


Subject(s)
Adenosine Triphosphate/metabolism , Coenzymes/metabolism , Endosomal Sorting Complexes Required for Transport/metabolism , Protein Subunits/metabolism , Vacuolar Proton-Translocating ATPases/metabolism , ATPases Associated with Diverse Cellular Activities , Amino Acid Sequence , Animals , Coenzymes/chemistry , Coenzymes/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Endosomal Sorting Complexes Required for Transport/chemistry , Endosomal Sorting Complexes Required for Transport/genetics , Gene Expression Regulation , Humans , Hydrolysis , Kinetics , Mice , Models, Molecular , Molecular Sequence Data , Mutation , Protein Multimerization , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Subunits/chemistry , Protein Subunits/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Sequence Homology, Amino Acid , Signal Transduction , Vacuolar Proton-Translocating ATPases/chemistry , Vacuolar Proton-Translocating ATPases/genetics
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