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Article ; Online: pH-dependent conformation of multimeric von Willebrand factor.

Smith, Ian W / Parker, Ernest T / Lollar, Pete

2023 Volume 7, Issue 11, Page(s) 2554–2557

MeSH term(s)	Humans ; von Willebrand Factor ; von Willebrand Diseases ; Factor VIII ; Molecular Conformation ; Hydrogen-Ion Concentration
Chemical Substances	von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022009359
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Article ; Online: Measurement of the Translational Diffusion Coefficient and Hydrodynamic Radius of Proteins by Dynamic Light Scattering.

Parker, Ernest T / Lollar, Pete

Bio-protocol

2021 Volume 11, Issue 20, Page(s) e4195

Abstract: Diffusion is a fundamental process in biological systems that governs the molecular collisions driving biochemical reactions and membrane and transport. Measurement of the diffusion coefficient and application of the Stokes-Einstein equation produces the ...

Abstract	Diffusion is a fundamental process in biological systems that governs the molecular collisions driving biochemical reactions and membrane and transport. Measurement of the diffusion coefficient and application of the Stokes-Einstein equation produces the hydrodynamic radius, which is a commonly used gauge of particle size. Additionally, measurement of the diffusion coefficient and the sedimentation coefficient, and application of the Svedberg equation, yields the molecular weight, which is particularly useful in the characterization of very large macromolecules. Dynamic light scattering (DLS) is the most common method to measure the diffusion coefficient of macromolecules. We describe a procedure to perform DLS measurements on monomeric bovine serum albumin (BSA) purified by size-exclusion chromatography using the Zetasizer Nano S particle size analyzer. We compare several analytical methods in existing software programs to estimate the diffusion coefficient of BSA (extrapolated to water at 20°C at infinite dilution,
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4195
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Article ; Online: Conformation of the von Willebrand factor/factor VIII complex in quasi-static flow.

Parker, Ernest T / Lollar, Pete

The Journal of biological chemistry

2021 Volume 296, Page(s) 100420

Abstract: Von Willebrand factor (VWF) is a plasma glycoprotein that circulates noncovalently bound to blood coagulation factor VIII (fVIII). VWF is a population of multimers composed of a variable number of ∼280 kDa monomers that is activated in shear flow to bind ...

Abstract	Von Willebrand factor (VWF) is a plasma glycoprotein that circulates noncovalently bound to blood coagulation factor VIII (fVIII). VWF is a population of multimers composed of a variable number of ∼280 kDa monomers that is activated in shear flow to bind collagen and platelet glycoprotein Ibα. Electron microscopy, atomic force microscopy, small-angle neutron scattering, and theoretical studies have produced a model in which the conformation of VWF under static conditions is a compact, globular "ball-of-yarn," implying strong, attractive forces between monomers. We performed sedimentation velocity (SV) analytical ultracentrifugation measurements on unfractionated VWF/fVIII complexes. There was a 20% per mg/ml decrease in the weight-average sedimentation coefficient, s
MeSH term(s)	Blood Platelets/metabolism ; Collagen ; Drug Combinations ; Factor VIII/isolation & purification ; Factor VIII/metabolism ; Factor VIII/pharmacology ; Factor VIII/physiology ; Humans ; Molecular Conformation ; Molecular Weight ; Plasma/chemistry ; Scattering, Small Angle ; Ultracentrifugation ; von Willebrand Factor/isolation & purification ; von Willebrand Factor/metabolism ; von Willebrand Factor/pharmacology ; von Willebrand Factor/physiology
Chemical Substances	Drug Combinations ; factor VIII, von Willebrand factor drug combination ; von Willebrand Factor ; Factor VIII (9001-27-8) ; Collagen (9007-34-5)
Language	English
Publishing date	2021-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.100420
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Article ; Online: Subunit Flexibility of Multimeric von Willebrand Factor/Factor VIII Complexes.

Parker, Ernest T / Haberichter, Sandra L / Lollar, Pete

ACS omega

2022 Volume 7, Issue 35, Page(s) 31183–31196

Abstract: Von Willebrand factor (VWF) is a plasma glycoprotein that participates in platelet adhesion and aggregation and serves as a carrier for blood coagulation factor VIII (fVIII). Plasma VWF consists of a population of multimers that range in molecular weight ...

Abstract	Von Willebrand factor (VWF) is a plasma glycoprotein that participates in platelet adhesion and aggregation and serves as a carrier for blood coagulation factor VIII (fVIII). Plasma VWF consists of a population of multimers that range in molecular weight from ∼ 0.55 MDa to greater than 10 MDa. The VWF multimer consists of a variable number of concatenated disulfide-linked ∼275 kDa subunits. We fractionated plasma-derived human VWF/fVIII complexes by size-exclusion chromatography at a pH of 7.4 and subjected them to analysis by sodium dodecyl sulfate agarose gel electrophoresis, sedimentation velocity analytical ultracentrifugation (SV AUC), dynamic light scattering (DLS), and multi-angle light scattering (MALS). Weight-average molecular weights,
Language	English
Publishing date	2022-08-25
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.2c03389
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Article ; Online: Nanobody activator improves sensitivity of the VWF activity assay to multimer size.

Liang, Qian / Parker, Ernest T / Dean, Gabrielle / Karpen, Matthew S / Wu, Yujia / Wang, Xuefeng / Di Paola, Jorge / Maier, Cheryl L / Meeks, Shannon L / Lollar, Pete / Sidonio, Robert F / Li, Renhao

Journal of thrombosis and haemostasis : JTH

2024

Abstract: Background: The activity of von Willebrand factor (VWF) in facilitating platelet adhesion and aggregation correlates with its multimer size. Traditional ristocetin-dependent functional assays lack sensitivity to multimers sizes. Recently nanobodies ... ...

Abstract	Background: The activity of von Willebrand factor (VWF) in facilitating platelet adhesion and aggregation correlates with its multimer size. Traditional ristocetin-dependent functional assays lack sensitivity to multimers sizes. Recently nanobodies targeting the autoinhibitory module and activating VWF were identified. Objective: To develop an assay that can differentiate the platelet-binding activity of VWF multimers. Methods: An ELISA-based assay (VWF:GPIbNab) utilizing a VWF-activating nanobody was developed. Recombinant VWF (rVWF), plasma-derived VWF (pdVWF), and selected gel-filtrated fractions of pdVWF, were evaluated for VWF antigen and activity levels. A linear regression model was developed to estimate the specific activity of VWF multimers. Results: Of three activating nanobodies tested, 6C11 with the lowest activation effect exhibited the highest sensitivity for high-molecular-weight multimers (HMWMs) of VWF. VWF:GPIbNab utilizing 6C11 (VWF:GPIbNab Conclusions: The VWF:GPIbNab
Language	English
Publishing date	2024-05-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2024.04.015
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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
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Article ; Online: Removal of single-site N-linked glycans on factor VIII alters binding of domain-specific monoclonal antibodies.

Ito, Jasmine / Baldwin, Wallace Hunter / Cox, Courtney / Healey, John F / Parker, Ernest T / Legan, Emily R / Li, Renhao / Gill, Surinder / Batsuli, Glaivy

Journal of thrombosis and haemostasis : JTH

2021 Volume 20, Issue 3, Page(s) 574–588

Abstract: Background: A portion of individuals with hemophilia A develop neutralizing antibodies called inhibitors to glycoprotein factor VIII (FVIII). There are multiple risk factors that contribute to the risk of inhibitor formation. However, knowledge of the ... ...

Abstract	Background: A portion of individuals with hemophilia A develop neutralizing antibodies called inhibitors to glycoprotein factor VIII (FVIII). There are multiple risk factors that contribute to the risk of inhibitor formation. However, knowledge of the role of FVIII asparagine (N)-linked glycosylation in FVIII immunity is limited. Objective: To evaluate the effect of site-specific N-linked glycan removal on FVIII biochemical properties, endocytosis by murine bone marrow-derived dendritic cells (BMDCs), and antibody responses. Methods: Four recombinant B domain-deleted (BDD) FVIII variants with single-site amino acid substitutions to remove N-linked glycans were produced for experimental assays. Results: BDD FVIII-N41G, FVIII-N239A, FVIII-N1810A, and FVIII-N2118A with confirmed removal of N-linked glycans and similar glycosylation profiles to BDD FVIII were produced. There were no differences in thrombin activation or von Willebrand factor binding of FVIII variants compared with BDD FVIII; however, reduced FVIII expression, activity, and specific activity was observed with all variants. BDD FVIII-N41G and FVIII-N1810A had reduced uptake by BMDCs, but there were no differences in antibody development in immunized hemophilia A mice compared with BDD FVIII. Half of a repertoire of 12 domain-specific FVIII MAbs had significantly reduced binding to ≥1 FVIII variant with a 50% decrease in A1 domain MAb 2-116 binding to FVIII-N239A. Conclusions: Modifications of FVIII N-linked glycans reduced FVIII endocytosis by BMDCs and binding of domain-specific FVIII MAbs, but did not alter de novo antibody production in hemophilia A mice, suggesting that N-glycans do not significantly contribute to inhibitor formation.
MeSH term(s)	Animals ; Antibodies, Monoclonal ; Factor VIII ; Hemophilia A ; Mice ; Polysaccharides ; von Willebrand Factor/metabolism
Chemical Substances	Antibodies, Monoclonal ; Polysaccharides ; von Willebrand Factor ; Factor VIII (9001-27-8)
Language	English
Publishing date	2021-12-17
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.15616
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Article ; Online: Neutralizing Antibodies Against Factor VIII Can Occur Through a Non-Germinal Center Pathway.

Patel, Seema R / Lundgren, Taran S / Baldwin, Wallace Hunter / Cox, Courtney / Parker, Ernest T / Healey, John F / Jajosky, Ryan P / Zerra, Patricia E / Josephson, Cassandra D / Doering, Christopher B / Stowell, Sean R / Meeks, Shannon L

Frontiers in immunology

2022 Volume 13, Page(s) 880829

Abstract: Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal ... ...

Abstract	Humoral immunity to factor VIII (FVIII) represents a significant challenge for the treatment of patients with hemophilia A. Current paradigms indicate that neutralizing antibodies against FVIII (inhibitors) occur through a classical CD4 T cell, germinal center (GC) dependent process. However, clinical observations suggest that the nature of the immune response to FVIII may differ between patients. While some patients produce persistent low or high inhibitor titers, others generate a transient response. Moreover, FVIII reactive memory B cells are only detectable in some patients with sustained inhibitor titers. The determinants regulating the type of immune response a patient develops, let alone how the immune response differs in these patients remains incompletely understood. One hypothesis is that polymorphisms within immunoregulatory genes alter the underlying immune response to FVIII, and thereby the inhibitor response. Consistent with this, studies report that inhibitor titers to FVIII differ in animals with the same
MeSH term(s)	Animals ; Antibodies, Neutralizing ; Factor VIII ; Germinal Center/metabolism ; Hemophilia A ; Hemostatics ; Humans ; Mice
Chemical Substances	Antibodies, Neutralizing ; Hemostatics ; Factor VIII (9001-27-8)
Language	English
Publishing date	2022-05-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.880829
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Article: Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity.

Zerra, Patricia E / Parker, Ernest T / Baldwin, Wallace Hunter / Healey, John F / Patel, Seema R / McCoy, James W / Cox, Courtney / Stowell, Sean R / Meeks, Shannon L

Biomedicines

2022 Volume 10, Issue 7

Abstract: The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target ... ...

Abstract	The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323-339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA
Language	English
Publishing date	2022-07-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10071724
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Article: Contribution of A1 subunit residue Q316 in thrombin-activated factor VIII to A2 subunit dissociation.

Parker, Ernest T / Lollar, Pete

Biochemistry

2007 Volume 46, Issue 34, Page(s) 9737–9742

Abstract: Blood coagulation factor VIII (fVIII) is activated by thrombin to form an A1/A2/A3-C1-C2 heterotrimer, which functions as a cofactor for factor IXa during intrinsic pathway factor X activation. Human thrombin-activated fVIII (fVIIIa) decays rapidly ... ...

Abstract	Blood coagulation factor VIII (fVIII) is activated by thrombin to form an A1/A2/A3-C1-C2 heterotrimer, which functions as a cofactor for factor IXa during intrinsic pathway factor X activation. Human thrombin-activated fVIII (fVIIIa) decays rapidly because of first-order dissociation of the A2 subunit, which may function to regulate the coagulation mechanism. The three fVIII A domains each consist of two cupredoxin-like subdomains. Substitution of the COOH-terminal A1 subdomain of porcine fVIIIa, which decays more slowly than human fVIIIa, reduces the dissociation rate constant for fVIIIa decay. Examination of a human fVIII A1-A2-A3 homology model [Pemberton, S., et al. (1997) Blood 89, 2413-2421) revealed a possible interaction between Q316 in the FG helix of the COOH-terminal A1 subdomain and M539 in the FG helix of the NH2-terminal A2 subdomain, which are sites where human and porcine fVIII differ. Decays of purified recombinant human and porcine fVIIIa and the human fVIIIa mutants Q316H, M539L and Q316H/M539L were compared at 23 and 37 degrees C. The decay rates of the Q316H and Q316H/M539L mutants, but not the M539L mutant, were significantly slower than human fVIIIa. These results indicate that the FG helix of the COOH-terminal A1 cupredoxin-like subdomain of fVIII may be under selective pressure by the requirements of hemostatic balance.
MeSH term(s)	Amino Acid Sequence ; Factor VIIIa/chemistry ; Factor VIIIa/genetics ; Factor VIIIa/metabolism ; Humans ; Kinetics ; Models, Chemical ; Molecular Sequence Data ; Mutation/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits ; Sequence Homology, Amino Acid ; Thrombin/pharmacology
Chemical Substances	Protein Subunits ; Factor VIIIa (72175-66-7) ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2007-08-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/bi700941w
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