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  1. Article ; Online: The secret afterlife of platelets.

    Arce, Nicholas A / Li, Renhao

    Haematologica

    2019  Volume 104, Issue 9, Page(s) 1699–1701

    MeSH term(s) Blood Platelets ; Thrombin
    Chemical Substances Thrombin (EC 3.4.21.5)
    Language English
    Publishing date 2019-08-24
    Publishing country Italy
    Document type Editorial ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2019.224170
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Autoinhibitory module underlies species difference in shear activation of von Willebrand factor.

    Arce, Nicholas A / Liu, Yi / Chen, Wenchun / Zhang, X Frank / Li, Renhao

    Journal of thrombosis and haemostasis : JTH

    2022  Volume 20, Issue 11, Page(s) 2686–2696

    Abstract: Background: Von Willebrand factor (VWF) is a multimeric plasma protein that bridges the gap between vessel injury and platelet capture at high shear rates. Under high shear or tension, VWF can become activated upon the unfolding of its autoinhibitory ... ...

    Abstract Background: Von Willebrand factor (VWF) is a multimeric plasma protein that bridges the gap between vessel injury and platelet capture at high shear rates. Under high shear or tension, VWF can become activated upon the unfolding of its autoinhibitory module (AIM). AIM unfolding exposes the A1 domain, allowing for binding to platelet glycoprotein (GP)Ibα to initiate primary hemostasis. The characteristics of the AIM and its inhibitory properties within mouse VWF are unknown.
    Objectives: To determine and characterize the autoinhibitory properties of mouse VWF.
    Methods: Recombinant mouse VWF A1 fragments containing or lacking the flanking regions around the A1 domain were generated. We tested the ability of these fragments to bind to human or mouse GPIbα and platelets. We compared the unfolding of mouse AIM-A1 to human AIM-A1 by single-molecule force spectroscopy.
    Results: Recombinant mouse AIM-A1 binds with higher affinity to GPIbα than its human counterpart. Recombinant mouse proteins lacking part of the AIM show increased binding to GPIbα. Activated A1 fragments lacking the AIM can effectively agglutinate platelets across the species barrier. Using single-molecule force spectroscopy, we determined that the mouse AIM unfolds under forces similar to the human AIM. Additionally, the human AIM paired with mouse A1 largely recapitulates the behavior of human AIM-A1.
    Conclusions: Our results suggest that the regulation of VWF-GPIbα binding has been specifically tuned to work optimally in different rheological architectures. Differences in the AIM sequence may contribute to the difference in VWF shear response between human and mice.
    MeSH term(s) Humans ; Mice ; Animals ; von Willebrand Factor/metabolism ; Species Specificity ; Protein Binding ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; Blood Platelets/metabolism ; Hemostasis ; Recombinant Proteins/chemistry
    Chemical Substances von Willebrand Factor ; Platelet Glycoprotein GPIb-IX Complex ; Recombinant Proteins
    Language English
    Publishing date 2022-08-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.15837
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module.

    Arce, Nicholas A / Markham-Lee, Zoe / Liang, Qian / Najmudin, Shabir / Legan, Emily R / Dean, Gabrielle / Su, Ally J / Wilson, Moriah S / Sidonio, Robert F / Lollar, Pete / Emsley, Jonas / Li, Renhao

    Blood

    2024  Volume 143, Issue 19, Page(s) 1992–2004

    Abstract: Abstract: Activation of von Willebrand factor (VWF) is a tightly controlled process governed primarily by local elements around its A1 domain. Recent studies suggest that the O-glycosylated sequences flanking the A1 domain constitute a discontinuous and ...

    Abstract Abstract: Activation of von Willebrand factor (VWF) is a tightly controlled process governed primarily by local elements around its A1 domain. Recent studies suggest that the O-glycosylated sequences flanking the A1 domain constitute a discontinuous and force-sensitive autoinhibitory module (AIM), although its extent and conformation remains controversial. Here, we used a targeted screening strategy to identify 2 groups of nanobodies. One group, represented by clone 6D12, is conformation insensitive and binds the N-terminal AIM (NAIM) sequence that is distal from A1; 6D12 activates human VWF and induces aggregation of platelet-rich plasma at submicromolar concentrations. The other group, represented by clones Nd4 and Nd6, is conformation sensitive and targets the C-terminal AIM (CAIM). Nd4 and Nd6 inhibit ristocetin-induced platelet aggregation and reduce VWF-mediated platelet adhesion under flow. A crystal structure of Nd6 in complex with AIM-A1 shows a novel conformation of both CAIM and NAIM that are primed to interact, providing a model of steric hindrance stabilized by the AIM as the mechanism for regulating GPIbα binding to VWF. Hydrogen-deuterium exchange mass spectrometry analysis shows that binding of 6D12 induces the exposure of the GPIbα-binding site in the A1 domain, but binding of inhibitory nanobodies reduces it. Overall, these results suggest that the distal portion of NAIM is involved in specific interactions with CAIM, and binding of nanobodies to the AIM could either disrupt its conformation to activate VWF or stabilize its conformation to upkeep VWF autoinhibition. These reported nanobodies could facilitate future studies of VWF functions and related pathologies.
    MeSH term(s) von Willebrand Factor/metabolism ; von Willebrand Factor/chemistry ; Humans ; Single-Domain Antibodies/pharmacology ; Single-Domain Antibodies/chemistry ; Single-Domain Antibodies/metabolism ; Platelet Aggregation/drug effects ; Protein Conformation ; Protein Domains ; Protein Binding ; Platelet Adhesiveness/drug effects ; Crystallography, X-Ray ; Animals ; Blood Platelets/metabolism
    Chemical Substances von Willebrand Factor ; Single-Domain Antibodies
    Language English
    Publishing date 2024-02-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2023022038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Type 2B von Willebrand disease mutations differentially perturb autoinhibition of the A1 domain.

    Legan, Emily R / Liu, Yi / Arce, Nicholas A / Parker, Ernest T / Lollar, Pete / Zhang, X Frank / Li, Renhao

    Blood

    2022  Volume 141, Issue 10, Page(s) 1221–1232

    Abstract: Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder in which a subset of point mutations in the von Willebrand factor (VWF) A1 domain and recently identified autoinhibitory module (AIM) cause spontaneous binding to glycoprotein Ibα ( ... ...

    Abstract Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder in which a subset of point mutations in the von Willebrand factor (VWF) A1 domain and recently identified autoinhibitory module (AIM) cause spontaneous binding to glycoprotein Ibα (GPIbα) on the platelet surface. All reported type 2B VWD mutations share this enhanced binding; however, type 2B VWD manifests as variable bleeding complications and platelet levels in patients, depending on the underlying mutation. Understanding how these mutations localizing to a similar region can result in such disparate patient outcomes is essential for detailing our understanding of VWF regulatory and activation mechanisms. In this study, we produced recombinant glycosylated AIM-A1 fragments bearing type 2B VWD mutations and examined how each mutation affects the A1 domain's thermodynamic stability, conformational dynamics, and biomechanical regulation of the AIM. We found that the A1 domain with mutations associated with severe bleeding occupy a higher affinity state correlating with enhanced flexibility in the secondary GPIbα-binding sites. Conversely, mutation P1266L, associated with normal platelet levels, has similar proportions of high-affinity molecules to wild-type (WT) but shares regions of solvent accessibility with both WT and other type 2B VWD mutations. V1316M exhibited exceptional instability and solvent exposure compared with all variants. Lastly, examination of the mechanical stability of each variant revealed variable AIM unfolding. Together, these studies illustrate that the heterogeneity among type 2B VWD mutations is evident in AIM-A1 fragments.
    MeSH term(s) Humans ; Binding Sites ; Blood Platelets/metabolism ; Mutation ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; von Willebrand Disease, Type 2/genetics ; von Willebrand Factor/chemistry ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
    Chemical Substances Platelet Glycoprotein GPIb-IX Complex ; von Willebrand Factor
    Language English
    Publishing date 2022-12-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2022017239
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: A wild boar cathelicidin peptide derivative inhibits severe acute respiratory syndrome coronavirus-2 and its drifted variants.

    von Beck, Troy / Navarrete, Karla / Arce, Nicholas A / Gao, Mu / Dale, Gordon A / Davis-Gardner, Meredith E / Floyd, Katharine / Mena Hernandez, Luis / Mullick, Nikita / Vanderheiden, Abigail / Skountzou, Ioanna / Kuchipudi, Suresh V / Saravanan, Rathi / Li, Renhao / Skolnick, Jeffrey / Suthar, Mehul S / Jacob, Joshy

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 14650

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a clear threat to humanity. It has infected over 200 million and killed 4 million people worldwide, and infections continue with no end in sight. To control the pandemic, multiple ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a clear threat to humanity. It has infected over 200 million and killed 4 million people worldwide, and infections continue with no end in sight. To control the pandemic, multiple effective vaccines have been developed, and global vaccinations are in progress. However, the virus continues to mutate. Even when full vaccine coverage is achieved, vaccine-resistant mutants will likely emerge, thus requiring new annual vaccines against drifted variants analogous to influenza. A complimentary solution to this problem could be developing antiviral drugs that inhibit SARS CoV-2 and its drifted variants. Host defense peptides represent a potential source for such an antiviral as they possess broad antimicrobial activity and significant diversity across species. We screened the cathelicidin family of peptides from 16 different species for antiviral activity and identified a wild boar peptide derivative that inhibits SARS CoV-2. This peptide, which we named Yongshi and means warrior in Mandarin, acts as a viral entry inhibitor. Following the binding of SARS-CoV-2 to its receptor, the spike protein is cleaved, and heptad repeats 1 and 2 multimerize to form the fusion complex that enables the virion to enter the cell. A deep learning-based protein sequence comparison algorithm and molecular modeling suggest that Yongshi acts as a mimetic to the heptad repeats of the virus, thereby disrupting the fusion process. Experimental data confirm the binding of Yongshi to the heptad repeat 1 with a fourfold higher affinity than heptad repeat 2 of SARS-CoV-2. Yongshi also binds to the heptad repeat 1 of SARS-CoV-1 and MERS-CoV. Interestingly, it inhibits all drifted variants of SARS CoV-2 that we tested, including the alpha, beta, gamma, delta, kappa and omicron variants.
    MeSH term(s) Humans ; Cathelicidins ; SARS-CoV-2 ; COVID-19 ; Antiviral Agents
    Chemical Substances Cathelicidins ; Antiviral Agents
    Language English
    Publishing date 2023-09-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-41850-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module.

    Arce, Nicholas A / Cao, Wenpeng / Brown, Alexander K / Legan, Emily R / Wilson, Moriah S / Xu, Emma-Ruoqi / Berndt, Michael C / Emsley, Jonas / Zhang, X Frank / Li, Renhao

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 2360

    Abstract: Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX ... ...

    Abstract Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX complex. Here we show that the shear-responsive element controlling VWF activation resides in the discontinuous autoinhibitory module (AIM) flanking A1. Application of tensile force in a single-molecule setting induces cooperative unfolding of the AIM to expose A1. The AIM-unfolding force is lowered by truncating either N- or C-terminal AIM region, type 2B VWD mutations, or binding of a ristocetin-mimicking monoclonal antibody, all of which could activate A1. Furthermore, the AIM is mechanically stabilized by the nanobody that comprises caplacizumab, the only FDA-approved anti-thrombotic drug to-date that targets VWF. Thus, the AIM is a mechano-regulator of VWF activity. Its conformational dynamics may define the extent of VWF autoinhibition and subsequent activation under force.
    MeSH term(s) Antibodies, Monoclonal/pharmacology ; Biomechanical Phenomena ; Crystallography, X-Ray ; Humans ; In Vitro Techniques ; Models, Molecular ; Mutation ; Platelet Aggregation/drug effects ; Protein Conformation ; Protein Domains ; Protein Stability ; Protein Unfolding ; Ristocetin/pharmacology ; Single Molecule Imaging ; Single-Domain Antibodies/pharmacology ; Tensile Strength ; von Willebrand Factor/chemistry ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
    Chemical Substances Antibodies, Monoclonal ; Single-Domain Antibodies ; von Willebrand Factor ; Ristocetin (1404-55-3) ; caplacizumab (2R27AB6766)
    Language English
    Publishing date 2021-04-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-22634-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Desialylation of O-glycans activates von Willebrand factor by destabilizing its autoinhibitory module.

    Voos, Kayleigh M / Cao, Wenpeng / Arce, Nicholas A / Legan, Emily R / Wang, Yingchun / Shajahan, Asif / Azadi, Parastoo / Lollar, Pete / Zhang, Xiaohui Frank / Li, Renhao

    Journal of thrombosis and haemostasis : JTH

    2021  Volume 20, Issue 1, Page(s) 196–207

    Abstract: Background: The binding of the A1 domain of von Willebrand factor (VWF) to platelet receptor glycoprotein (GP)Ibα defines the VWF activity in hemostasis. Recent studies suggest that sequences flanking A1 form cooperatively an autoinhibitory module (AIM) ...

    Abstract Background: The binding of the A1 domain of von Willebrand factor (VWF) to platelet receptor glycoprotein (GP)Ibα defines the VWF activity in hemostasis. Recent studies suggest that sequences flanking A1 form cooperatively an autoinhibitory module (AIM) that reduces the accessibility of the GPIbα binding site on A1. Application of a tensile force induces unfolding of the AIM. Desialylation induces spontaneous binding of plasma VWF to platelets. Most O-glycans in VWF are located around the A1 domain. Removing certain O-glycans in the flanking sequences by site-directed mutagenesis enhances A1 binding to GPIbα and produces an effect similar to type 2B von Willebrand disease in animals.
    Objectives: To understand if and how desialylation of O-glycans in the flanking sequences increases A1 activity.
    Methods: A recombinant AIM-A1 fragment encompassing VWF residues 1238-1493 and only O-glycans was treated with neuraminidase to produce desialylated protein. The glycan structure, dynamics, stability, and function of the desialylated protein was characterized by biochemical and biophysical methods and compared to the sialylated fragment.
    Results: Asialo-AIM-A1 exhibited increased binding activity and induced more apparent platelet aggregation than its sialylated counterpart. It exhibited a lower melting temperature, and increased hydrogen-deuterium exchange rates at residues near the secondary GPIbα binding site and the N-terminal flanking sequence. Asialo-AIM-A1 is less mechanically stable than sialo-AIM-A1, with its unstressed unfolding rate approximately 3-fold greater than the latter.
    Conclusions: Desialylation of O-glycans around A1 increases its activity by destabilizing the AIM.
    MeSH term(s) Animals ; Blood Platelets/metabolism ; Platelet Aggregation ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; Polysaccharides ; Protein Binding ; von Willebrand Disease, Type 2/metabolism ; von Willebrand Factor/metabolism
    Chemical Substances Platelet Glycoprotein GPIb-IX Complex ; Polysaccharides ; von Willebrand Factor
    Language English
    Publishing date 2021-09-26
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.15528
    Database MEDical Literature Analysis and Retrieval System OnLINE

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