ADAMTS13, lucky to have a hydrophobic pocket

Zheng, X. Long

doi:10.1182/blood-2015-01-621235

Cited by 2 publications

(2 citation statements)

References 11 publications

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“…Deficiency of ADAMTS13 activity, caused by either mutations in the ADAMTS13 gene or by inhibitory autoantibodies against ADAMTS13, results in the accumulation of ultra-large VWF (ULVWF) in plasma, leading to excessive platelet aggregation and disseminated VWF/platelet-rich thrombus formation, which is the characteristic feature of thrombotic thrombocytopenic purpura (TTP)[1, 4–7]. Mild to moderate deficiency of ADAMTS13 activity or increased ratios of VWF to ADAMTS13 have been shown to be risk factors for the development of systemic inflammation, myocardial or cerebral infarction, preeclampsia or eclampsia, and cerebral malaria[8–11].…”

Section: Introductionmentioning

confidence: 99%

AFM Imaging Reveals Multiple Conformational States of ADAMTS13

et al. 2019

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BackgroundADAMTS13 (A disintegrin and metalloprotease with a thrombospondin type 1 motif 13) cleaves Von Willebrand factor (VWF) to regulate its size, thereby preventing aberrant platelet aggregation and thrombus. Deficiency of ADAMTS13 caused by either genetic mutations or by inhibitory autoantibodies against ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP). Recently, ADAMTS13 was reported to adopt a “closed” conformation with lower activity and an “open” one resulting from the engagements of VWF D4-CK domains or antibodies to the distal domains of ADAMTS13, or mutations in its spacer domain. These engagements or mutations increase ADAMTS13 activity by ~ 2.5-fold. However, it is less known whether the conformation of ADAMTS13 is dynamic or stable.ResultsWild type ADAMTS13 (WT-ADAMTS13) and the gain-of-function variant (GOF-ADAMTS13) with five mutations (R568K / F592Y / R660K / Y661F / Y665F) in spacer domain were imaged by atomic force microscopy (AFM) at pH 6 and pH 7.5. The data revealed that at both pH 6 and pH 7.5, WT-ADAMTS13 adopted two distinct conformational states (state I and state II), while an additional state (state III) was observed in GOF-ADAMTS13. In the present study, we propose that state I is the “closed” conformation, state III is the “open” one, and state II is an intermediate one. Comparing to pH 7.5, the percentages of state II of WT-ADAMTS13 and state III of GOF-ADAMTS13 increased at pH 6, with the decrease in the state I for WT-ADAMTS13 and state I and state II for GOF-ADAMTS13, suggesting lower pH extended the conformation of ADAMTS13.ConclusionBoth WT- and GOF-ADAMTS13 exist multiple conformational states and lower pH might alter the tertiary structure and/or disrupt the intra-domain interactions, increasing the flexibility of ADAMTS13 molecules.Electronic supplementary materialThe online version of this article (10.1186/s13036-018-0102-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

AFM Imaging Reveals Multiple Conformational States of ADAMTS13

et al. 2019

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“…However, cleavage cannot occur unless A2 has been unfolded, either by tensile force 13 – 15 or by chaotropic agents 16 , to induce the exposure of the scissile bond. The single metalloprotease domain is unable to cleave this peptide bond, while the truncated mutant MDTCS is considered to be the minimum unit that possesses comparable proteolytic activity as wild type 17 – 20 . However, the proximal carboxyl-terminal domains of ADAMTS13 are also required for recognition and cleavage 21 .…”

Section: Introductionmentioning

confidence: 99%

Prediction of spacer-α6 complex: a novel insight into binding of ADAMTS13 with A2 domain of von Willebrand factor under forces

Fang

Lin

Fang

et al. 2018

Sci Rep

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Force-regulated cleavage of A2 domain of von Willebrand factor (vWF) by ADAMTS13 is a key event in preventing thrombotic thrombocytopenic purpura (TTP). Recognition and cleavage depend on cooperative and modular contacts between several ADAMTS13 subdomains and discrete segments of vWF A2 domain. Spacer domain of ADAMTS13 contains an important exosite interacting with α6 helix of unfold A2 domain, but it remains unclear whether stretching of α6 regulates binding to spacer. To understand the molecular mechanism underlying the interactions between spacer and α6 under stretching, we successfully predicted spacer-α6 complex by a novel computer strategy combined the steered molecular dynamics (SMD) and flexible docking techniques. This strategy included three steps: (1) constant-velocity SMD simulation of α6; (2) zero-velocity SMD simulations of α6, and (3) flexible dockings of α6 to spacer. In our spacer-α6 complex model, 13 key residues, six in α6 and seven in spacer, were identified. Our data demonstrated a biphasic extension-regulated binding of α6 to spacer. The binding strength of the complex increased with α6 extension until it reaches its optimum of 0.25 nm, and then decreased as α6 extension further increased, meaning that spacer is in favor to binding with a partially extended α6, which may contribute to the optimal contact and proteolysis. Changes of interface area and intermolecular salt bridge may serve as the molecular basis for this characteristic. These findings provide a novel insight into mechano-chemical regulation on interaction between ADAMTS13 and vWF A2 domain under forces.

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ADAMTS13, lucky to have a hydrophobic pocket

Cited by 2 publications

References 11 publications

AFM Imaging Reveals Multiple Conformational States of ADAMTS13

AFM Imaging Reveals Multiple Conformational States of ADAMTS13

Prediction of spacer-α6 complex: a novel insight into binding of ADAMTS13 with A2 domain of von Willebrand factor under forces

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