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  1. Article ; Online: Molecular Interaction between Distal C-Terminal Domain of the CB

    Singh, Pratishtha / Ganjiwale, Anjali / Howlett, Allyn C / Cowsik, Sudha M

    Journal of chemical information and modeling

    2019  Volume 59, Issue 12, Page(s) 5294–5303

    Abstract: We have investigated the structure of the distal C-terminal domain of the of the CB ...

    Abstract We have investigated the structure of the distal C-terminal domain of the of the CB
    MeSH term(s) Amino Acid Sequence ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Models, Molecular ; Protein Binding ; Protein Domains ; Protein Structure, Secondary ; Receptor, Cannabinoid, CB1/chemistry ; Receptor, Cannabinoid, CB1/metabolism
    Chemical Substances Carrier Proteins ; Receptor, Cannabinoid, CB1
    Language English
    Publishing date 2019-12-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.9b00948
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 1: study protocol for a hybrid type 2 effectiveness-implementation cluster-randomized trial.

    Sarfan, Laurel D / Agnew, Emma R / Diaz, Marlen / Dong, Lu / Fisher, Krista / Spencer, Julia M / Howlett, Shayna A / Hache, Rafael Esteva / Callaway, Catherine A / Kilbourne, Amy M / Buysse, Daniel J / Harvey, Allison G

    Trials

    2023  Volume 24, Issue 1, Page(s) 198

    Abstract: ... for Sleep and Circadian Dysfunction (TranS-C) implemented in community mental health centers (CMHCs). TranS ... C was designed to target a range of SMI diagnoses by addressing a probable mechanism and predictor ... of SMI: sleep and circadian problems. We will investigate whether adapting TranS-C to fit CMHC contexts ...

    Abstract Background: Serious mental illness (SMI) can have devastating consequences. Unfortunately, many patients with SMI do not receive evidence-based psychological treatment (EBPTs) in routine practice settings. One barrier is poor "fit" between EBPTs and contexts in which they are implemented. The present study will evaluate implementation and effectiveness outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) implemented in community mental health centers (CMHCs). TranS-C was designed to target a range of SMI diagnoses by addressing a probable mechanism and predictor of SMI: sleep and circadian problems. We will investigate whether adapting TranS-C to fit CMHC contexts improves providers' perceptions of fit and patient outcomes.
    Methods: TranS-C will be implemented in at least ten counties in California, USA (N = 96 providers; N = 576 clients), via facilitation. CMHC sites are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each county, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will compare TranS-C (combined Adapted and Standard) with UC-DT on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms. Sleep and circadian problems will also be tested as a mediator between treatment condition (combined TranS-C versus UC-DT) and functional impairment/psychiatric symptoms. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to provider perceptions of fit. Aim 3 will evaluate whether the relation between TranS-C treatment condition (Adapted versus Standard) and patient outcomes is mediated by better provider perceptions of fit in the Adapted condition. Exploratory analyses will (1) compare Adapted versus Standard TranS-C on patient perceptions of credibility/improvement and select PhenX Toolkit outcomes and (2) evaluate possible moderators.
    Discussion: This trial has the potential to (a) expand support for TranS-C, a promising transdiagnostic treatment delivered to patients with SMI in CMHCs; (b) take steps toward addressing challenges faced by providers in delivering EBPTs (i.e., high caseloads, complex patients, poor fit); and (c) advance evidence on causal strategies (i.e., adapting treatments to fit context) in implementation science.
    Trial registration: Clinicaltrials.gov NCT04154631. Registered on 6 November 2019. https://clinicaltrials.gov/ct2/show/NCT04154631.
    MeSH term(s) Humans ; Mental Health ; Mental Disorders/diagnosis ; Mental Disorders/therapy ; Mental Disorders/psychology ; Sleep ; Implementation Science ; Randomized Controlled Trials as Topic
    Language English
    Publishing date 2023-03-17
    Publishing country England
    Document type Clinical Trial Protocol ; Journal Article
    ZDB-ID 2040523-6
    ISSN 1745-6215 ; 1468-6694 ; 1745-6215
    ISSN (online) 1745-6215
    ISSN 1468-6694 ; 1745-6215
    DOI 10.1186/s13063-023-07148-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Correction: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS‑C) for serious mental illness in community mental health part 1: study protocol for a hybrid type 2 effectiveness‑implementation cluster‑randomized trial.

    Sarfan, Laurel D / Agnew, Emma R / Diaz, Marlen / Dong, Lu / Fisher, Krista / Spencer, Julia M / Howlett, Shayna A / Hache, Rafael Esteva / Callaway, Catherine A / Kilbourne, Amy M / Buysse, Daniel J / Harvey, Allison G

    Trials

    2023  Volume 24, Issue 1, Page(s) 529

    Language English
    Publishing date 2023-08-14
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2040523-6
    ISSN 1745-6215 ; 1468-6694 ; 1745-6215
    ISSN (online) 1745-6215
    ISSN 1468-6694 ; 1745-6215
    DOI 10.1186/s13063-023-07479-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 1

    Laurel D. Sarfan / Emma R. Agnew / Marlen Diaz / Lu Dong / Krista Fisher / Julia M. Spencer / Shayna A. Howlett / Rafael Esteva Hache / Catherine A. Callaway / Amy M. Kilbourne / Daniel J. Buysse / Allison G. Harvey

    Trials, Vol 24, Iss 1, Pp 1-

    study protocol for a hybrid type 2 effectiveness-implementation cluster-randomized trial

    2023  Volume 18

    Abstract: ... for Sleep and Circadian Dysfunction (TranS-C) implemented in community mental health centers (CMHCs). TranS ... C was designed to target a range of SMI diagnoses by addressing a probable mechanism and predictor ... of SMI: sleep and circadian problems. We will investigate whether adapting TranS-C to fit CMHC contexts ...

    Abstract Abstract Background Serious mental illness (SMI) can have devastating consequences. Unfortunately, many patients with SMI do not receive evidence-based psychological treatment (EBPTs) in routine practice settings. One barrier is poor “fit” between EBPTs and contexts in which they are implemented. The present study will evaluate implementation and effectiveness outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) implemented in community mental health centers (CMHCs). TranS-C was designed to target a range of SMI diagnoses by addressing a probable mechanism and predictor of SMI: sleep and circadian problems. We will investigate whether adapting TranS-C to fit CMHC contexts improves providers’ perceptions of fit and patient outcomes. Methods TranS-C will be implemented in at least ten counties in California, USA (N = 96 providers; N = 576 clients), via facilitation. CMHC sites are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each county, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will compare TranS-C (combined Adapted and Standard) with UC-DT on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms. Sleep and circadian problems will also be tested as a mediator between treatment condition (combined TranS-C versus UC-DT) and functional impairment/psychiatric symptoms. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to provider perceptions of fit. Aim 3 will evaluate whether the relation between TranS-C treatment condition (Adapted versus Standard) and patient outcomes is mediated by better provider perceptions of fit in the Adapted condition. Exploratory analyses will (1) compare Adapted versus Standard TranS-C on patient perceptions of credibility/improvement and select PhenX Toolkit outcomes and (2) evaluate possible moderators. Discussion This trial has the potential to (a) expand support for ...
    Keywords Transdiagnostic ; Sleep ; Circadian ; Serious mental illness ; Implementation ; Adaptation ; Medicine (General) ; R5-920
    Subject code 150
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 2

    Catherine A. Callaway / Laurel D. Sarfan / Emma R. Agnew / Lu Dong / Julia M. Spencer / Rafael Esteva Hache / Marlen Diaz / Shayna A. Howlett / Krista R. Fisher / Heather E. Hilmoe Yates / Eric Stice / Amy M. Kilbourne / Daniel J. Buysse / Allison G. Harvey

    Trials, Vol 24, Iss 1, Pp 1-

    study protocol for a hybrid type 2 effectiveness-implementation cluster-randomized trial using train-the-trainer

    2023  Volume 19

    Abstract: ... TranS-C)—delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained ... and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C ... facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each CMHC ...

    Abstract Abstract Background Train-the-trainer (TTT) is a promising method for implementing evidence-based psychological treatments (EBPTs) in community mental health centers (CMHCs). In TTT, expert trainers train locally embedded individuals (i.e., Generation 1 providers) to deliver an EBPT, who then train others (i.e., Generation 2 providers). The present study will evaluate implementation and effectiveness outcomes of an EBPT for sleep and circadian dysfunction—the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C)—delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C to fit CMHC contexts improves Generation 2 (a) patient outcomes and (b) providers’ perceptions of fit. Methods TTT will be implemented in nine CMHCs in California, USA (N = 60 providers; N = 130 patients) via facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each CMHC, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will assess the effectiveness of TranS-C (combined Adapted and Standard), compared to UC-DT, on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms for Generation 2 patients. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to Generation 2 providers’ perceptions of fit. Aim 3 will evaluate whether Generation 2 providers’ perceived fit mediates the relation between TranS-C treatment condition and patient outcomes. Exploratory analyses will (1) evaluate whether the effectiveness of TranS-C for patient outcomes is moderated by generation, (2) compare Adapted and Standard TranS-C on patient perceptions of credibility/improvement and PhenX Toolkit outcomes (e.g., substance use, suicidality), and (3) evaluate other possible moderators. Discussion This trial has potential to (a) inform the ...
    Keywords Train-the-trainer ; Transdiagnostic ; Sleep ; Circadian ; Serious mental illness ; Implementation ; Medicine (General) ; R5-920
    Language English
    Publishing date 2023-08-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 2: study protocol for a hybrid type 2 effectiveness-implementation cluster-randomized trial using train-the-trainer.

    Callaway, Catherine A / Sarfan, Laurel D / Agnew, Emma R / Dong, Lu / Spencer, Julia M / Hache, Rafael Esteva / Diaz, Marlen / Howlett, Shayna A / Fisher, Krista R / Yates, Heather E Hilmoe / Stice, Eric / Kilbourne, Amy M / Buysse, Daniel J / Harvey, Allison G

    Trials

    2023  Volume 24, Issue 1, Page(s) 503

    Abstract: ... TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained ... and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C ... via facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C ...

    Abstract Background: Train-the-trainer (TTT) is a promising method for implementing evidence-based psychological treatments (EBPTs) in community mental health centers (CMHCs). In TTT, expert trainers train locally embedded individuals (i.e., Generation 1 providers) to deliver an EBPT, who then train others (i.e., Generation 2 providers). The present study will evaluate implementation and effectiveness outcomes of an EBPT for sleep and circadian dysfunction-the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C to fit CMHC contexts improves Generation 2 (a) patient outcomes and (b) providers' perceptions of fit.
    Methods: TTT will be implemented in nine CMHCs in California, USA (N = 60 providers; N = 130 patients) via facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each CMHC, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will assess the effectiveness of TranS-C (combined Adapted and Standard), compared to UC-DT, on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms for Generation 2 patients. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to Generation 2 providers' perceptions of fit. Aim 3 will evaluate whether Generation 2 providers' perceived fit mediates the relation between TranS-C treatment condition and patient outcomes. Exploratory analyses will (1) evaluate whether the effectiveness of TranS-C for patient outcomes is moderated by generation, (2) compare Adapted and Standard TranS-C on patient perceptions of credibility/improvement and PhenX Toolkit outcomes (e.g., substance use, suicidality), and (3) evaluate other possible moderators.
    Discussion: This trial has potential to (a) inform the process of embedding local trainers and supervisors to expand delivery of a promising transdiagnostic treatment for sleep and circadian dysfunction, (b) add to the growing body of TTT literature by evaluating TTT outcomes with a novel treatment and population, and (c) advance our understanding of providers' perceptions of EBPT "fit" across TTT generations.
    Trial registration: ClinicalTrials.gov identifier NCT05805657 . Registered on April 10, 2023.
    MeSH term(s) Humans ; Mental Health ; Treatment Outcome ; Mental Disorders/diagnosis ; Mental Disorders/therapy ; Mental Disorders/psychology ; Sleep ; Community Mental Health Centers ; Randomized Controlled Trials as Topic
    Language English
    Publishing date 2023-08-07
    Publishing country England
    Document type Clinical Trial Protocol ; Journal Article
    ZDB-ID 2040523-6
    ISSN 1745-6215 ; 1468-6694 ; 1745-6215
    ISSN (online) 1745-6215
    ISSN 1468-6694 ; 1745-6215
    DOI 10.1186/s13063-023-07523-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) for serious mental illness in community mental health part 2: Study protocol for a hybrid type 2 effectiveness-implementation cluster- randomized trial using train-the-trainer.

    Callaway, Catherine A / Sarfan, Laurel D / Agnew, Emma R / Dong, Lu / Spencer, Julia M / Hache, Rafael Esteva / Diaz, Marlen / Howlett, Shayna A / Fisher, Krista R / Yates, Heather E Hilmoe / Stice, Eric / Kilbourne, Amy M / Buysse, Daniel J / Harvey, Allison G

    Research square

    2023  

    Abstract: ... TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained ... and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C ... of TTT literature by evaluating TTT outcomes with a novel treatment and population, and (c) advancing ...

    Abstract Background: Train-the-trainer (TTT) is a promising method for implementing evidence-based psychological treatments (EBPTs) in community mental health centers (CMHCs). In TTT, expert trainers train locally embedded individuals (i.e., Generation 1 providers) to deliver an EBPT, who then train others (i.e., Generation 2 providers). The present study will evaluate implementation and effectiveness outcomes of an EBPT for sleep and circadian dysfunction-the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C to fit CMHC contexts improves Generation 2 (a) patient outcomes (b) providers' perceptions of fit.
    Methods: TTT will be implemented in nine CMHCs in California, United States (
    Discussion: This trial has potential to inform the process of (a) embedding local trainers and supervisors to expand delivery of a promising transdiagnostic treatment for sleep and circadian dysfunction, (b) adding to the growing body of TTT literature by evaluating TTT outcomes with a novel treatment and population, and (c) advancing our understanding of providers' perceptions of EBPT 'fit' across TTT generations.
    Trial registration: Clinicaltrials.gov identifier: NCT05805657. Registered on April 10, 2023. https://clinicaltrials.gov/ct2/show/NCT05805657.
    Language English
    Publishing date 2023-06-17
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-2943787/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils.

    Zlatic, Courtney O / Mao, Yu / Todorova, Nevena / Mok, Yee-Foong / Howlett, Geoffrey J / Yarovsky, Irene / Gooley, Paul R / Griffin, Michael D W

    The FEBS journal

    2018  Volume 285, Issue 15, Page(s) 2799–2812

    Abstract: Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits ... consistent with a core cross-β structure comprising the C-terminal 58-76 region. Molecular dynamics ...

    Abstract Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits in vivo and is an independent risk factor for cardiovascular disease. Lipid-free apoC-II readily self-assembles into twisted-ribbon amyloid fibrils but forms straight, rod-like amyloid fibrils in the presence of low concentrations of micellar phospholipids. Charge mutations exerted significantly different effects on rod-like fibril formation compared to their effects on twisted-ribbon fibril formation. For instance, the double mutant, K30D-D69K apoC-II, readily formed twisted-ribbon fibrils, while the rate of rod-like fibril formation in the presence of micellar phospholipid was negligible. Structural analysis of rod-like apoC-II fibrils, using hydrogen-deuterium exchange and NMR analysis showed exchange protection consistent with a core cross-β structure comprising the C-terminal 58-76 region. Molecular dynamics simulations of fibril arrangements for this region favoured a parallel cross-β structure. X-ray fibre diffraction data for aligned rod-like fibrils showed a major meridional spacing at 4.6 Å and equatorial spacings at 9.7, 23.8 and 46.6 Å. The latter two equatorial spacings are not observed for aligned twisted-ribbon fibrils and are predicted for a model involving two cross-β fibrils in an off-set antiparallel structure with four apoC-II units per rise of the β-sheet. This model is consistent with the mutational effects on rod-like apoC-II fibril formation. The lipid-dependent polymorphisms exhibited by apoC-II fibrils could determine the properties of apoC-II in renal amyloid deposits and their potential role in the development of cardiovascular disease.
    MeSH term(s) Acrylamide/chemistry ; Amyloid/chemistry ; Amyloid/metabolism ; Apolipoprotein C-II/chemistry ; Apolipoprotein C-II/genetics ; Apolipoprotein C-II/metabolism ; Cardiovascular Diseases/genetics ; Deuterium Exchange Measurement ; Humans ; Microscopy, Electron, Transmission ; Molecular Dynamics Simulation ; Mutation ; X-Ray Diffraction
    Chemical Substances Amyloid ; Apolipoprotein C-II ; Acrylamide (20R035KLCI)
    Language English
    Publishing date 2018-06-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.14517
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  9. Article: The Role of Lipid in Misfolding and Amyloid Fibril Formation by Apolipoprotein C-II.

    Ryan, Timothy M / Mok, Yee-Foong / Howlett, Geoffrey J / Griffin, Michael D W

    Advances in experimental medicine and biology

    2015  Volume 855, Page(s) 157–174

    Abstract: ... to aggregate into amyloid fibrils. Apolipoprotein C-II (apoC-II) is a member of the apolipoprotein family ...

    Abstract Apolipoproteins are a key component of lipid transport in the circulatory system and share a number of structural features that facilitate this role. When bound to lipoprotein particles, these proteins are relatively stable. However, in the absence of lipids they display conformational instability and a propensity to aggregate into amyloid fibrils. Apolipoprotein C-II (apoC-II) is a member of the apolipoprotein family that has been well characterised in terms of its misfolding and aggregation. In the absence of lipid, and at physiological ionic strength and pH, apoC-II readily forms amyloid fibrils with a twisted ribbon-like morphology that are amenable to a range of biophysical and structural analyses. Consistent with its lipid binding function, the misfolding and aggregation of apoC-II are substantially affected by the presence of lipid. Short-chain phospholipids at submicellar concentrations significantly accelerate amyloid formation by inducing a tetrameric form of apoC-II that can nucleate fibril aggregation. Conversely, phospholipid micelles and bilayers inhibit the formation of apoC-II ribbon-type fibrils, but induce slow formation of amyloid with a distinct straight fibril morphology. Our studies of the effects of lipid at each stage of amyloid formation, detailed in this chapter, have revealed complex behaviour dependent on the chemical nature of the lipid molecule, its association state, and the protein:lipid ratio.
    MeSH term(s) Amyloid/metabolism ; Apolipoprotein C-II/chemistry ; Apolipoprotein C-II/metabolism ; Kinetics ; Lipids/physiology ; Micelles ; Protein Conformation ; Protein Folding
    Chemical Substances Amyloid ; Apolipoprotein C-II ; Lipids ; Micelles
    Language English
    Publishing date 2015
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-3-319-17344-3_7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Intra- and Intersubunit Ion-Pair Interactions Determine the Ability of Apolipoprotein C-II Mutants To Form Hybrid Amyloid Fibrils.

    Todorova, Nevena / Zlatic, Courtney O / Mao, Yu / Yarovsky, Irene / Howlett, Geoffrey J / Gooley, Paul R / Griffin, Michael D W

    Biochemistry

    2017  Volume 56, Issue 12, Page(s) 1757–1767

    Abstract: ... with lipid surfaces. In the absence of lipid, human apolipoprotein (apo) C-II also forms well-defined ...

    Abstract The apolipoprotein family is structurally defined by amphipathic α-helical regions that interact with lipid surfaces. In the absence of lipid, human apolipoprotein (apo) C-II also forms well-defined amyloid fibrils with cross-β structure. Formation of this β-structure is accompanied by the burial of two charged residues, K30 and D69, that form an ion-pair within the amyloid fibril core. Molecular dynamics (MD) simulations indicate these buried residues form both intra- and intersubunit ion-pair interactions that stabilize the fibril. Mutations of the ion-pair (either K30D or D69K) reduce fibril stability and prevent fibril formation by K30D apoC-II under standard conditions. We investigated whether mixing K30D apoC-II with other mutants would overcome this loss of fibril forming ability. Co-incubation of equimolar mixtures of K30D apoC-II with wild-type, D69K, or double-mutant (K30D/D69K) apoC-II promoted the incorporation of K30D apoC-II into hybrid fibrils with increased stability. MD simulations showed an increase in the number of intersubunit ion-pair interactions accompanied the increased stability of the hybrid fibrils. These results demonstrate the important role of both intra- and intersubunit charge interactions in stabilizing apoC-II amyloid fibrils, a process that may be a key factor in determining the general ability of proteins to form amyloid fibrils.
    MeSH term(s) Amyloid/chemistry ; Amyloid/genetics ; Amyloid/metabolism ; Amyloidogenic Proteins/chemistry ; Amyloidogenic Proteins/genetics ; Amyloidogenic Proteins/metabolism ; Apolipoprotein C-II/chemistry ; Apolipoprotein C-II/genetics ; Apolipoprotein C-II/metabolism ; Aspartic Acid/chemistry ; Aspartic Acid/metabolism ; Gene Expression ; Humans ; Lysine/chemistry ; Lysine/metabolism ; Molecular Dynamics Simulation ; Mutation ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Subunits/chemistry ; Protein Subunits/genetics ; Protein Subunits/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Static Electricity
    Chemical Substances Amyloid ; Amyloidogenic Proteins ; Apolipoprotein C-II ; Protein Subunits ; Recombinant Proteins ; Aspartic Acid (30KYC7MIAI) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2017-03-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/acs.biochem.6b01146
    Database MEDical Literature Analysis and Retrieval System OnLINE

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