Simulated Thermal Unfolding of the von Willebrand Factor A Domains

Chen, Wei; Lou, Jizhong; Zhu, Cheng

doi:10.1007/s12195-010-0117-z

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…Following crystal structure determinations of WT A1 (44), two type 2B variants (R1306Q and I1309V) (45), and their complexes with GPIba (46-48), many molecular dynamics simulations have been performed (23,(49)(50)(51)(52). However, the starting structures and those resulting from these simulations are representative of only local conformational changes within the native state ensemble, and the forced dissociation of the complex cannot account for misfolded conformations.…”

Section: Discussionmentioning

confidence: 99%

Misfolding of vWF to Pathologically Disordered Conformations Impacts the Severity of von Willebrand Disease

Tischer

Madde

Moon‐Tasson

et al. 2014

Biophysical Journal

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The primary hemostatic von Willebrand factor (vWF) functions to sequester platelets from rheological blood flow and mediates their adhesion to damaged subendothelium at sites of vascular injury. We have surveyed the effect of 16 disease-causing mutations identified in patients diagnosed with the bleeding diathesis disorder, von Willebrand disease (vWD), on the structure and rheology of vWF A1 domain adhesiveness to the platelet GPIbα receptor. These mutations have a dynamic phenotypical range of bleeding from lack of platelet adhesion to severe thrombocytopenia. Using new rheological tools in combination with classical thermodynamic, biophysical, and spectroscopic metrics, we establish a high propensity of the A1 domain to misfold to pathological molten globule conformations that differentially alter the strength of platelet adhesion under shear flow. Rheodynamic analysis establishes a quantitative rank order between shear-rate-dependent platelet-translocation pause times that linearly correlate with clinically reported measures of patient platelet counts and the severity of thrombocytopenia. These results suggest that specific secondary structure elements remaining in these pathological conformations of the A1 domain regulate GPIbα binding and the strength of vWF-platelet interactions, which affects the vWD functional phenotype and the severity of thrombocytopenia.

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Section: Discussionmentioning

confidence: 99%

Misfolding of vWF to Pathologically Disordered Conformations Impacts the Severity of von Willebrand Disease

Tischer

Madde

Moon‐Tasson

et al. 2014

Biophysical Journal

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“…40 The unfolding of the central b-sheet of vWF-A2 is proposed to start from its edges and then propagate into its center. 13 The allostery of P-selectin lectin (Lec) domain followed by an epithelial growth factor (EGF)-like domain is recently visualized using free MDS. 61 These simulations shed light on the question that what aspects, such as topology, hydrogen-bonding patterns, and core interactions, determine the mechanical properties of a protein.…”

Section: Molecular Dynamic Simulation Of Molecular Biomechanicsmentioning

confidence: 99%

Advances in Experiments and Modeling in Micro- and Nano-Biomechanics: A Mini Review

et al. 2011

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Abstract-Recent advances in micro-and nano-technologies and high-end computing have enabled the development of new experimental and modeling approaches to study biomechanics at the micro-and nano-scales that were previously not possible. These new cutting-edge approaches are contributing toward our understanding in emerging areas such as mechanobiology and mechanochemistry. Another important potential contribution lies in translational medicine, since biomechanical studies at the cellular and molecular levels have direct relevance in areas such disease diagnosis, nano-medicine and drug delivery. Thus, the developed experimental and modeling approaches are critical in elucidating important mechanistic insights in both basic sciences and clinical treatment. While it is hard to cover all the recent advances in this mini-review, we focus on several important approaches. For experimental techniques, we review the assays involving shear flow, cellular imaging, microbead, microcontact printing, and micropillars at the micro-scale, and micropipette aspiration, optical tweezers, parallel flow chamber, and atomic force microscopy at the nano-scale. In modeling and simulations, we outline the theoretical modeling for actin dynamics in migrating cell and actin-based cell motility in cellular mechanics, as well as the receptor-ligand binding in cell adhesion and the application of free, steered, and flow molecular dynamics simulations in molecular biomechanics. Relevant scientific issues and applications are also discussed.

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A common mechanism by which type 2A von Willebrand disease mutations enhance ADAMTS13 proteolysis revealed with a von Willebrand factor A2 domain FRET construct

et al. 2017

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Rheological forces in the blood trigger the unfolding of von Willebrand factor (VWF) and its A2 domain, exposing the scissile bond for proteolysis by ADAMTS13. Under quiescent conditions, the scissile bond is hidden by the folded structure due to the stabilisation provided by the structural specialisations of the VWF A2 domain, a vicinal disulphide bond, a calcium binding site and a N1574-glycan.The reduced circulating high MW multimers of VWF in patients with type 2A von Willebrand disease (VWD) may be associated with mutations within the VWF A2 domain and this is attributed to enhanced ADAMTS13 proteolysis. We investigated 11 VWF A2 domain variants identified in patients with type 2A VWD. In recombinant full-length VWF, enhanced ADAMTS13 proteolysis was detected for all of the expressed variants in the presence of urea-induced denaturation. A subset of the FLVWF variants displayed enhanced proteolysis in the absence of urea. The mechanism of enhancement was investigated using a novel VWF A2 domain FRET construct. In the absence of induced unfolding, 7/8 of the expressed mutants exhibited a disrupted domain fold, causing spatial separation of the N- and C- termini. Three of the type 2A mutants were not secreted when studied within the VWF A2 domain FRET construct. Urea denaturation revealed for all 8 secreted mutants reduced unfolding cooperativity and stability of the VWF A2 domain. As folding stability was progressively disrupted, proteolysis by ADAMTS13 increased. Due to the range of folding stabilities and wide distribution of VWF A2 domain mutations studied, we conclude that these mutations disrupt regulated folding of the VWF A2 domain. They enhance unfolding by inducing separation of N- and C-termini, thereby promoting a more open conformation that reveals its binding sites for ADAMTS13 and the scissile bond.

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Simulated Thermal Unfolding of the von Willebrand Factor A Domains

Cited by 3 publications

References 28 publications

Misfolding of vWF to Pathologically Disordered Conformations Impacts the Severity of von Willebrand Disease

Misfolding of vWF to Pathologically Disordered Conformations Impacts the Severity of von Willebrand Disease

Advances in Experiments and Modeling in Micro- and Nano-Biomechanics: A Mini Review

A common mechanism by which type 2A von Willebrand disease mutations enhance ADAMTS13 proteolysis revealed with a von Willebrand factor A2 domain FRET construct

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