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  1. Artikel ; Online: Probing the drivers of

    Howard, Matthew K / Miller, Karlie R / Sohn, Brian S / Ryan, Jeremy J / Xu, Andy / Jackrel, Meredith E

    mBio

    2023  Band 14, Heft 4, Seite(n) e0058723

    Abstract: Phenol-soluble modulins (PSMs) are the primary proteinaceous component ... ...

    Abstract Phenol-soluble modulins (PSMs) are the primary proteinaceous component of
    Mesh-Begriff(e) Humans ; Staphylococcus aureus/metabolism ; Methicillin-Resistant Staphylococcus aureus/genetics ; Methicillin-Resistant Staphylococcus aureus/metabolism ; Saccharomyces cerevisiae/metabolism ; Biofilms ; Amyloid/genetics ; Amyloid/metabolism ; Staphylococcal Infections/microbiology ; Peptides/metabolism ; Phenols/metabolism
    Chemische Substanzen Amyloid ; Peptides ; Phenols
    Sprache Englisch
    Erscheinungsdatum 2023-05-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.00587-23
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Rosace: a robust deep mutational scanning analysis framework employing position and mean-variance shrinkage.

    Rao, Jingyou / Xin, Ruiqi / Macdonald, Christian / Howard, Matthew K / Estevam, Gabriella O / Yee, Sook Wah / Wang, Mingsen / Fraser, James S / Coyote-Maestas, Willow / Pimentel, Harold

    Genome biology

    2024  Band 25, Heft 1, Seite(n) 138

    Abstract: Deep mutational scanning (DMS) measures the effects of thousands of genetic variants in a protein simultaneously. The small sample size renders classical statistical methods ineffective. For example, p-values cannot be correctly calibrated when treating ... ...

    Abstract Deep mutational scanning (DMS) measures the effects of thousands of genetic variants in a protein simultaneously. The small sample size renders classical statistical methods ineffective. For example, p-values cannot be correctly calibrated when treating variants independently. We propose Rosace, a Bayesian framework for analyzing growth-based DMS data. Rosace leverages amino acid position information to increase power and control the false discovery rate by sharing information across parameters via shrinkage. We also developed Rosette for simulating the distributional properties of DMS. We show that Rosace is robust to the violation of model assumptions and is more powerful than existing tools.
    Mesh-Begriff(e) Bayes Theorem ; Humans ; Software ; Mutation ; DNA Mutational Analysis/methods
    Sprache Englisch
    Erscheinungsdatum 2024-05-24
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/s13059-024-03279-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species.

    Chen, Sheng / Puri, Anuradhika / Bell, Braxton / Fritsche, Joseph / Palacios, Hector H / Balch, Maurie / Sprunger, Macy L / Howard, Matthew K / Ryan, Jeremy J / Haines, Jessica N / Patti, Gary J / Davis, Albert A / Jackrel, Meredith E

    Nature communications

    2024  Band 15, Heft 1, Seite(n) 2436

    Abstract: Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial ... ...

    Abstract Parkinson's disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer's disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 expression promotes α-syn seeding. HTRA1 remodels α-syn fibrils by targeting the NAC domain, the key domain catalyzing α-syn amyloidogenesis. Finally, HTRA1 detoxifies α-syn fibrils and prevents formation of hyperphosphorylated α-syn accumulations in primary neurons. Our findings suggest that HTRA1 may be a therapeutic target for a range of neurodegenerative disorders.
    Mesh-Begriff(e) Humans ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism ; Amyloid/metabolism ; High-Temperature Requirement A Serine Peptidase 1/genetics ; High-Temperature Requirement A Serine Peptidase 1/metabolism ; Parkinson Disease/genetics ; Parkinson Disease/metabolism ; Lewy Bodies/metabolism
    Chemische Substanzen alpha-Synuclein ; Amyloid ; High-Temperature Requirement A Serine Peptidase 1 (EC 3.4.21.-)
    Sprache Englisch
    Erscheinungsdatum 2024-03-18
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-46538-8
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel: Molecular basis of proton-sensing by G protein-coupled receptors.

    Howard, Matthew K / Hoppe, Nicholas / Huang, Xi-Ping / Macdonald, Christian B / Mehrota, Eshan / Grimes, Patrick Rockefeller / Zahm, Adam / Trinidad, Donovan D / English, Justin / Coyote-Maestas, Willow / Manglik, Aashish

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Three proton-sensing G protein-coupled receptors (GPCRs), GPR4, GPR65, and GPR68, respond to changes in extracellular pH to regulate diverse physiology and are implicated in a wide range of diseases. A central challenge in determining how protons ... ...

    Abstract Three proton-sensing G protein-coupled receptors (GPCRs), GPR4, GPR65, and GPR68, respond to changes in extracellular pH to regulate diverse physiology and are implicated in a wide range of diseases. A central challenge in determining how protons activate these receptors is identifying the set of residues that bind protons. Here, we determine structures of each receptor to understand the spatial arrangement of putative proton sensing residues in the active state. With a newly developed deep mutational scanning approach, we determined the functional importance of every residue in proton activation for GPR68 by generating ~9,500 mutants and measuring effects on signaling and surface expression. This unbiased screen revealed that, unlike other proton-sensitive cell surface channels and receptors, no single site is critical for proton recognition in GPR68. Instead, a network of titratable residues extend from the extracellular surface to the transmembrane region and converge on canonical class A GPCR activation motifs to activate proton-sensing GPCRs. More broadly, our approach integrating structure and unbiased functional interrogation defines a new framework for understanding the rich complexity of GPCR signaling.
    Sprache Englisch
    Erscheinungsdatum 2024-04-18
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.04.17.590000
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Profiling the proximal proteome of the activated μ-opioid receptor.

    Polacco, Benjamin J / Lobingier, Braden T / Blythe, Emily E / Abreu, Nohely / Khare, Prachi / Howard, Matthew K / Gonzalez-Hernandez, Alberto J / Xu, Jiewei / Li, Qiongyu / Novy, Brandon / Naing, Zun Zar Chi / Shoichet, Brian K / Coyote-Maestas, Willow / Levitz, Joshua / Krogan, Nevan J / Von Zastrow, Mark / Hüttenhain, Ruth

    Nature chemical biology

    2024  

    Abstract: The μ-opioid receptor (μOR) represents an important target of therapeutic and abused drugs. So far, most understanding of μOR activity has focused on a subset of known signal transducers and regulatory molecules. Yet μOR signaling is coordinated by ... ...

    Abstract The μ-opioid receptor (μOR) represents an important target of therapeutic and abused drugs. So far, most understanding of μOR activity has focused on a subset of known signal transducers and regulatory molecules. Yet μOR signaling is coordinated by additional proteins in the interaction network of the activated receptor, which have largely remained invisible given the lack of technologies to interrogate these networks systematically. Here we describe a proteomics and computational approach to map the proximal proteome of the activated μOR and to extract subcellular location, trafficking and functional partners of G-protein-coupled receptor (GPCR) activity. We demonstrate that distinct opioid agonists exert differences in the μOR proximal proteome mediated by endocytosis and endosomal sorting. Moreover, we identify two new μOR network components, EYA4 and KCTD12, which are recruited on the basis of receptor-triggered G-protein activation and might form a previously unrecognized buffering system for G-protein activity broadly modulating cellular GPCR signaling.
    Sprache Englisch
    Erscheinungsdatum 2024-03-25
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-024-01588-3
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: Functional analysis of proposed substrate-binding residues of Hsp104.

    Howard, Matthew K / Sohn, Brian S / von Borcke, Julius / Xu, Andy / Jackrel, Meredith E

    PloS one

    2020  Band 15, Heft 3, Seite(n) e0230198

    Abstract: Hsp104 is a hexameric AAA+ yeast disaggregase capable of solubilizing disordered aggregates and amyloid. Hsp104 couples ATP hydrolysis to polypeptide translocation through its central channel. Substrate binding by Hsp104 is mediated primarily by two ... ...

    Abstract Hsp104 is a hexameric AAA+ yeast disaggregase capable of solubilizing disordered aggregates and amyloid. Hsp104 couples ATP hydrolysis to polypeptide translocation through its central channel. Substrate binding by Hsp104 is mediated primarily by two conserved tyrosine residues in nucleotide binding domain (NBD) 1 and NBD2. Recent structural studies have revealed that an additional tyrosine residue (Y650) located in NBD2 appears to contact substrate and may play an important role in Hsp104 function. Here, we functionally analyze the properties of this proposed Hsp104 -substrate interaction. We find that Y650 is not essential for Hsp104 to confer thermotolerance. Supporting these findings, in a potentiated Hsp104 variant background, the Y650A mutation does not abolish potentiation. However, modulation of this site does have subtle effects on the activity of this potentiated Hsp104 variant. We therefore suggest that while Y650 is not essential for Hsp104 function, its modulation may be useful for fine-tuning Hsp104 properties.
    Mesh-Begriff(e) Adenosine Triphosphate/metabolism ; Cryoelectron Microscopy/methods ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Models, Molecular ; Protein Binding/genetics ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Structure-Activity Relationship
    Chemische Substanzen HSP70 Heat-Shock Proteins ; Heat-Shock Proteins ; Saccharomyces cerevisiae Proteins ; HsP104 protein, S cerevisiae (143012-44-6) ; Adenosine Triphosphate (8L70Q75FXE)
    Sprache Englisch
    Erscheinungsdatum 2020-03-10
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0230198
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Amyloidogenic propensity of self-assembling peptides and their adjuvant potential for use as DNA vaccines.

    Shrimali, Paresh C / Chen, Sheng / Das, Anirban / Dreher, Rachel / Howard, Matthew K / Ryan, Jeremy J / Buck, Jeremy / Kim, Darren / Sprunger, Macy L / Rudra, Jai S / Jackrel, Meredith E

    Acta biomaterialia

    2023  Band 169, Seite(n) 464–476

    Abstract: De novo designed peptides that self-assemble into cross-β rich fibrillar biomaterials have been pursued as an innovative platform for the development of adjuvant- and inflammation-free vaccines. However, they share structural and morphological properties ...

    Abstract De novo designed peptides that self-assemble into cross-β rich fibrillar biomaterials have been pursued as an innovative platform for the development of adjuvant- and inflammation-free vaccines. However, they share structural and morphological properties similar to amyloid species implicated in neurodegenerative diseases, which has been a long-standing concern for their successful translation. Here, we comprehensively characterize the amyloidogenic character of the amphipathic self-assembling cross-β peptide KFE
    Mesh-Begriff(e) Mice ; Animals ; Vaccines, DNA ; Peptides/chemistry ; Adjuvants, Immunologic/pharmacology ; CD8-Positive T-Lymphocytes ; Biocompatible Materials ; Mammals
    Chemische Substanzen Vaccines, DNA ; Peptides ; Adjuvants, Immunologic ; Biocompatible Materials
    Sprache Englisch
    Erscheinungsdatum 2023-08-14
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2173841-5
    ISSN 1878-7568 ; 1742-7061
    ISSN (online) 1878-7568
    ISSN 1742-7061
    DOI 10.1016/j.actbio.2023.08.015
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel: Oscillation responses to tropical Cyclone Gonu in northern Arabian Sea from a moored observing system

    Wang, Zhankun / DiMarco, Steven F / Stössel, Marion M / Zhang, Xiaoqian / Howard, Matthew K / du Vall, Ken

    Deep-Sea Research Part I. 2012 June, v. 64

    2012  

    Abstract: In June 2007, tropical Cyclone Gonu passed over an ocean observing system consisting of a deep autonomous mooring system in the northern Arabian Sea and a shallow cabled mooring system in the Sea of Oman. Gonu was the largest cyclone known to have ... ...

    Abstract In June 2007, tropical Cyclone Gonu passed over an ocean observing system consisting of a deep autonomous mooring system in the northern Arabian Sea and a shallow cabled mooring system in the Sea of Oman. Gonu was the largest cyclone known to have occurred in the Arabian Sea and to strike the Arabian Peninsula. The instruments on the moorings continuously recorded water velocities, temperature, conductivity, pressure, dissolved oxygen (DO) and turbidity at multiple depths and at hourly intervals during the storm. Near-inertial oscillations at all moorings from thermocline to seafloor are coincident with the arrival of Gonu. Sub-inertial oscillations with periods of 2–10 day are recorded at the post-storm relaxation stage of Gonu, primarily in the thermocline of the deep array and at the onshore regions of the shallow array. These oscillations consist of warm, saline water masses, likely originating from the Persian Gulf. Prominent 12.7-day sub-inertial waves, measured at a station ∼300km offshore, are bottom-intensified and have characteristics of baroclinic topographically trapped waves. Theoretical results from a topographically trapped wave model are in a good agreement with the observed 12.7-day waves at Murray Ridge. The wavelength of the 12.7-day waves is about 590km calculated from the dispersion relationship. Further analysis suggests that a resonant standing wave is responsible for trapping the 12.7-day wave energy inside the Sea of Oman basin. The observational results reported here are the first measurements of deepwater responses to a tropical cyclone in the Sea of Oman/Arabian Sea. Our study demonstrates the utility of sustained monitoring for studying the impact of extreme weather events on the ocean.
    Schlagwörter basins ; dissolved oxygen ; equipment ; hurricanes ; models ; monitoring ; saline water ; temperature ; turbidity ; water power ; wavelengths ; Arabian Sea ; Oman ; Persian Gulf
    Sprache Englisch
    Erscheinungsverlauf 2012-06
    Umfang p. 129-145.
    Erscheinungsort Elsevier Ltd
    Dokumenttyp Artikel
    ISSN 0967-0637
    DOI 10.1016/j.dsr.2012.02.005
    Datenquelle NAL Katalog (AGRICOLA)

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  9. Artikel: Continued Development of the Gulf of Mexico Coastal Ocean Observing System

    Jochens, Ann E / Luther, Mark / Meyers, Steve / Howden, Steven / Milbrant, Eric / Rybak, Alex / Dardeau, Michael / Hu, Lei / Park, Kyeong / Li, Chunyan / Campbell, Lisa / Speer, Kevin / Kirkpatrick, Gary / Currier, Robert / Kirkpatrick, Barbara / Jeffress, Gary / Rabalais, Nancy / Ivey, James / van Smirren, Jan /
    Howard, Matthew K

    Abstract: The overarching goal of this project is to build a robust, user-driven, sustained, operational Gulf of Mexico Coastal Ocean Observing System (GCOOS). The specific goals of this project are to maintain the existing GCOOS capabilities and, as funding ... ...

    Abstract The overarching goal of this project is to build a robust, user-driven, sustained, operational Gulf of Mexico Coastal Ocean Observing System (GCOOS). The specific goals of this project are to maintain the existing GCOOS capabilities and, as funding allows, to augment the existing observations to fill gaps and provide enhanced products and services. GCOOS capabilities include components to integrate data sets from diverse providers; assure consistency, quality, and accuracy of the data; create new products needed by users; and provide in a timely and efficient manner the data, products, and services needed by decision-makers, diverse stakeholders, and the public. Physical, meteorological, biogeochemical, and bathymetrical data are major components of the data system.
    Sprache Englisch
    Dokumenttyp Artikel
    Datenquelle AGRIS - International Information System for the Agricultural Sciences and Technology

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