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  1. Article ; Online: Greater than the sum of parts: Mechanisms of metabolic regulation by enzyme filaments.

    Hvorecny, Kelli L / Kollman, Justin M

    Current opinion in structural biology

    2023  Volume 79, Page(s) 102530

    Abstract: Recent work in structural biology is shedding light on how many of the enzymes of intermediary metabolism are self- and co-assembling into large, filamentous polymers or agglomerates to organize and regulate the complex and essential biochemical pathways ...

    Abstract Recent work in structural biology is shedding light on how many of the enzymes of intermediary metabolism are self- and co-assembling into large, filamentous polymers or agglomerates to organize and regulate the complex and essential biochemical pathways in cells. Filament assembly provides an additional layer of regulation by modulating the intrinsic allostery of the enzyme protomers which tunes activity in response to a variety of environmental cues. Enzyme filaments dynamically assemble and disassemble in response to changes in metabolite levels and environmental cues, shifting metabolic flux on a more rapid timescale than transcriptional or translational reprogramming. Here we present recent examples of high-resolution structures of filaments from proteins in intermediary metabolism and we discuss how filament assembly modulates the activities of these and other proteins.
    MeSH term(s) Proteins ; Cytoskeleton
    Chemical Substances Proteins
    Language English
    Publishing date 2023-01-27
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 1068353-7
    ISSN 1879-033X ; 0959-440X
    ISSN (online) 1879-033X
    ISSN 0959-440X
    DOI 10.1016/j.sbi.2023.102530
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3206: Show issues Location:
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  2. Article ; Online: Human PRPS1 filaments stabilize allosteric sites to regulate activity.

    Hvorecny, Kelli L / Hargett, Kenzee / Quispe, Joel D / Kollman, Justin M

    Nature structural & molecular biology

    2023  Volume 30, Issue 3, Page(s) 391–402

    Abstract: The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of ... ...

    Abstract The universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here we determine structures of human PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms.
    MeSH term(s) Humans ; Allosteric Site ; Mutation ; Ribose-Phosphate Pyrophosphokinase/genetics ; Ribose-Phosphate Pyrophosphokinase/metabolism
    Chemical Substances PRPS1 protein, human (EC 2.7.6.1) ; Ribose-Phosphate Pyrophosphokinase (EC 2.7.6.1)
    Language English
    Publishing date 2023-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/s41594-023-00921-z
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  3. Article: Molecular basis for the transcriptional regulation of an epoxide-based virulence circuit in

    He, Susu / Taher, Noor M / Hvorecny, Kelli L / Ragusa, Michael J / Bahl, Christopher D / Hickman, Alison B / Dyda, Fred / Madden, Dean R

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The opportunistic ... ...

    Abstract The opportunistic pathogen
    Language English
    Publishing date 2024-01-16
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.01.16.572601
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  4. Article ; Online: Toxoplasma gondii actin filaments are tuned for rapid disassembly and turnover.

    Hvorecny, Kelli L / Sladewski, Thomas E / De La Cruz, Enrique M / Kollman, Justin M / Heaslip, Aoife T

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 1840

    Abstract: The cytoskeletal protein actin plays a critical role in the pathogenicity of the intracellular parasite, Toxoplasma gondii, mediating invasion and egress, cargo transport, and organelle inheritance. Advances in live cell imaging have revealed extensive ... ...

    Abstract The cytoskeletal protein actin plays a critical role in the pathogenicity of the intracellular parasite, Toxoplasma gondii, mediating invasion and egress, cargo transport, and organelle inheritance. Advances in live cell imaging have revealed extensive filamentous actin networks in the Apicomplexan parasite, but there are conflicting data regarding the biochemical and biophysical properties of Toxoplasma actin. Here, we imaged the in vitro assembly of individual Toxoplasma actin filaments in real time, showing that native, unstabilized filaments grow tens of microns in length. Unlike skeletal muscle actin, Toxoplasma filaments intrinsically undergo rapid treadmilling due to a high critical concentration, fast monomer dissociation, and rapid nucleotide exchange. Cryo-EM structures of jasplakinolide-stabilized and native (i.e. unstabilized) filaments show an architecture like skeletal actin, with differences in assembly contacts in the D-loop that explain the dynamic nature of the filament, likely a conserved feature of Apicomplexan actin. This work demonstrates that evolutionary changes at assembly interfaces can tune the dynamic properties of actin filaments without disrupting their conserved structure.
    MeSH term(s) Animals ; Actins/metabolism ; Toxoplasma/metabolism ; Actin Cytoskeleton/metabolism ; Cytoskeleton/metabolism ; Parasites/metabolism
    Chemical Substances Actins
    Language English
    Publishing date 2024-02-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-46111-3
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  5. Article: Toxoplasma gondii

    Hvorecny, Kelli L / Sladewski, Thomas E / De La Cruz, Enrique M / Kollman, Justin M / Heaslip, Aoife T

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The cytoskeletal protein actin plays a critical role in the pathogenicity ... ...

    Abstract The cytoskeletal protein actin plays a critical role in the pathogenicity of
    Language English
    Publishing date 2023-08-30
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.29.555340
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  6. Article ; Online: Lysogenic host-virus interactions in SAR11 marine bacteria.

    Morris, Robert M / Cain, Kelsy R / Hvorecny, Kelli L / Kollman, Justin M

    Nature microbiology

    2020  Volume 5, Issue 8, Page(s) 1011–1015

    Abstract: Host-virus interactions structure microbial communities, drive biogeochemical cycles and enhance genetic diversity in ... ...

    Abstract Host-virus interactions structure microbial communities, drive biogeochemical cycles and enhance genetic diversity in nature
    MeSH term(s) Alphaproteobacteria/virology ; Bacteriophages/metabolism ; Genome, Viral ; Heterotrophic Processes ; Host Microbial Interactions ; Lysogeny ; Metagenomics ; Microbiota ; Oceans and Seas ; Prophages/metabolism ; Seawater/microbiology ; Seawater/virology ; Sequence Alignment ; Sequence Analysis, DNA ; Viral Proteins/genetics ; Viral Proteins/metabolism
    Chemical Substances Viral Proteins
    Language English
    Publishing date 2020-05-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-020-0725-x
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  7. Article ; Online: The Giardia ventrolateral flange is a lamellar membrane protrusion that supports attachment.

    Hardin, William R / Alas, Germain C M / Taparia, Nikita / Thomas, Elizabeth B / Steele-Ogus, Melissa C / Hvorecny, Kelli L / Halpern, Aaron R / Tůmová, Pavla / Kollman, Justin M / Vaughan, Joshua C / Sniadecki, Nathan J / Paredez, Alexander R

    PLoS pathogens

    2022  Volume 18, Issue 4, Page(s) e1010496

    Abstract: Attachment to the intestinal epithelium is critical to the lifestyle of the ubiquitous parasite Giardia lamblia. The ventrolateral flange is a sheet-like membrane protrusion at the interface between parasites and attached surfaces. This structure has ... ...

    Abstract Attachment to the intestinal epithelium is critical to the lifestyle of the ubiquitous parasite Giardia lamblia. The ventrolateral flange is a sheet-like membrane protrusion at the interface between parasites and attached surfaces. This structure has been implicated in attachment, but its role has been poorly defined. Here, we identified a novel actin associated protein with putative WH2-like actin binding domains we named Flangin. Flangin complexes with Giardia actin (GlActin) and is enriched in the ventrolateral flange making it a valuable marker for studying the flanges' role in Giardia biology. Live imaging revealed that the flange grows to around 1 μm in width after cytokinesis, then remains uniform in size during interphase, grows in mitosis, and is resorbed during cytokinesis. A flangin truncation mutant stabilizes the flange and blocks cytokinesis, indicating that flange disassembly is necessary for rapid myosin-independent cytokinesis in Giardia. Rho family GTPases are important regulators of membrane protrusions and GlRac, the sole Rho family GTPase in Giardia, was localized to the flange. Knockdown of Flangin, GlActin, and GlRac result in flange formation defects. This indicates a conserved role for GlRac and GlActin in forming membrane protrusions, despite the absence of canonical actin binding proteins that link Rho GTPase signaling to lamellipodia formation. Flangin-depleted parasites had reduced surface contact and when challenged with fluid shear force in flow chambers they had a reduced ability to remain attached, confirming a role for the flange in attachment. This secondary attachment mechanism complements the microtubule based adhesive ventral disc, a feature that may be particularly important during mitosis when the parental ventral disc disassembles in preparation for cytokinesis. This work supports the emerging view that Giardia's unconventional actin cytoskeleton has an important role in supporting parasite attachment.
    MeSH term(s) Actins/metabolism ; Animals ; Giardia/metabolism ; Giardia lamblia/genetics ; Giardia lamblia/metabolism ; Giardiasis/parasitology ; Parasites/metabolism ; Protozoan Proteins/genetics ; Protozoan Proteins/metabolism
    Chemical Substances Actins ; Protozoan Proteins
    Language English
    Publishing date 2022-04-28
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1010496
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  8. Article ; Online: A systematic CEN library of the Saccharomyces cerevisiae genome.

    Hvorecny, Kelli L / Prelich, Gregory

    Yeast (Chichester, England)

    2010  Volume 27, Issue 10, Page(s) 861–865

    Abstract: Progress in modern genetics is greatly facilitated by systematic resources that enable rapid and comprehensive analysis. Here we report the creation of a nearly complete systematic low-copy (CEN URA3) library of the Saccharomyces cerevisiae genome that ... ...

    Abstract Progress in modern genetics is greatly facilitated by systematic resources that enable rapid and comprehensive analysis. Here we report the creation of a nearly complete systematic low-copy (CEN URA3) library of the Saccharomyces cerevisiae genome that complements existing systematic high-copy libraries.
    MeSH term(s) Centromere/genetics ; Classification ; Gene Library ; Genes, Fungal ; Genome, Fungal ; Saccharomyces cerevisiae/genetics
    Language English
    Publishing date 2010-10
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 632636-5
    ISSN 1097-0061 ; 0749-503X
    ISSN (online) 1097-0061
    ISSN 0749-503X
    DOI 10.1002/yea.1783
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  9. Article: A systematic CEN library of the Saccharomyces cerevisiae genome

    Hvorecny, Kelli L / Prelich, Gregory

    Yeast. 2010 Oct., v. 27, no. 10

    2010  

    Abstract: Progress in modern genetics is greatly facilitated by systematic resources that enable rapid and comprehensive analysis. Here we report the creation of a nearly complete systematic low-copy (CEN URA3) library of the Saccharomyces cerevisiae genome that ... ...

    Abstract Progress in modern genetics is greatly facilitated by systematic resources that enable rapid and comprehensive analysis. Here we report the creation of a nearly complete systematic low-copy (CEN URA3) library of the Saccharomyces cerevisiae genome that complements existing systematic high-copy libraries. Copyright © 2010 John Wiley & Sons, Ltd.
    Keywords DNA libraries ; Saccharomyces cerevisiae ; genome
    Language English
    Dates of publication 2010-10
    Size p. 861-865.
    Publishing place John Wiley & Sons, Ltd.
    Document type Article
    ZDB-ID 632636-5
    ISSN 1097-0061 ; 0749-503X
    ISSN (online) 1097-0061
    ISSN 0749-503X
    DOI 10.1002/yea.1783
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    Z 4410: Show issues

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  10. Article: Visualizing the Mechanism of Epoxide Hydrolysis by the Bacterial Virulence Enzyme Cif

    Bahl, Christopher D / Hvorecny Kelli L / Morisseau Christophe / Gerber Scott A / Madden Dean R

    Biochemistry. 2016 Feb. 09, v. 55, no. 5

    2016  

    Abstract: The CFTR inhibitory factor (Cif) is an epoxide hydrolase (EH) virulence factor secreted by the bacterium Pseudomonas aeruginosa. Sequence alignments reveal a pattern of Cif-like substitutions that proved to be characteristic of a new subfamily of ... ...

    Abstract The CFTR inhibitory factor (Cif) is an epoxide hydrolase (EH) virulence factor secreted by the bacterium Pseudomonas aeruginosa. Sequence alignments reveal a pattern of Cif-like substitutions that proved to be characteristic of a new subfamily of bacterial EHs. At the same time, crystallographic and mutagenetic data suggest that EH activity is required for virulence and that Cif’s active site remains generally compatible with a canonical two-step EH mechanism. A hallmark of this mechanism is the formation of a covalent hydroxyalkyl-enzyme intermediate by nucleophilic attack. In several well-studied EHs, this intermediate has been captured at near stoichiometric levels, presumably reflecting rate-limiting hydrolysis. Here we show by mass spectrometry that only minimal levels of the expected intermediate can be trapped with WT Cif. In contrast, substantial amounts of intermediate are recovered from an active-site mutant (Cif-E153Q) that selectively targets the second, hydrolytic release step. Utilizing Cif-E153Q and a previously reported nucleophile mutant (Cif-D129S), we then captured Cif in the substrate-bound, hydroxyalkyl-intermediate, and product-bound states for 1,2-epoxyhexane, yielding the first crystallographic snapshots of an EH at these key stages along the reaction coordinate. Taken together, our data illuminate the proposed two-step hydrolytic mechanism of a new class of bacterial virulence factor. They also suggest that the failure of WT Cif to accumulate a covalent hydroxyalkyl-enzyme intermediate reflects an active-site chemistry in which hydrolysis is no longer the rate-limiting step, a noncanonical kinetic regime that may explain similar observations with a number of other EHs.
    Keywords Pseudomonas aeruginosa ; active sites ; bacteria ; epoxide hydrolase ; hydrolysis ; mass spectrometry ; mutants ; new subfamily ; sequence alignment ; virulence
    Language English
    Dates of publication 2016-0209
    Size p. 788-797.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021%2Facs.biochem.5b01229
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    Zs.A 217: Show issues Location:
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