Conformational plasticity of ADAMTS13 in hemostasis and autoimmunity

Abstract

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ADAMTS13 conformation is closed in non-immune acquired thrombotic thrombocytopenic purpura of unidentified pathophysiology

“…Since the 2010's, ADAMTS13 has been shown to have a conformational plasticity. 7 In healthy individuals, ADAMTS13 circulates in a latent "closed" conformation governed by a local latency due to an interaction between its CUB1-CUB2 domains and its S domain which contains a cryptic highly immunodominant epitope [8][9][10] and by a local latency due to the presence of a gatekeeper triad that blocks the active site. 10 Upon physiological binding to VWF, ADAMTS13 adopts a short lived, transient "open" conformation relieving global latency and allowing multiple interactions with VWF (molecular zipper model) and ultimately, its cleaving activity towards VWF (allosteric activation: relieving the gatekeeper triad).…”

“…This difference may be explained by some heterogeneity of ADAMTS13 Abs epitopes as a function of the idiopathic or non-idiopathic presentation of TTP, the Abs targeting the CS domains being likely the most efficient in maintaining an open ADAMTS13 conformation. 7,14,15 With or citrullination/oxidation of CUB or M/S domains residues, respectively) may imbalance the stability of intraand inter-domains interactions normally involved to maintain a closed conformation 7 . These last two mechanisms remain very speculative (especially the role of hyper-elevated VWF levels) because, in the absence of any TTP context, ADAMTS13 conformation was however found closed in patients with either sepsis 11 or COVID-19 infection.…”

“…7 : firstly and most likely, ADAMTS13 Abs (either IgG trapped in ADAMTS13/IgG immune complex or IgM/IgA class Abs) may be present in vivo but undetectable in vitro and these cases may correspond to underdiagnosed iTTP; secondly and less likely, hyper-elevated VWF levels commonly observed during infections and cancers, may prolong the physiologic opening of ADAMTS13; thirdly, post-translational modifications of ADAMTS13 structure induced by neutrophil-released substances during infections and inflammatory diseases (i.e. deglycosylation…”

“… 11-13 This difference may be explained by some heterogeneity of ADAMTS13 antibody epitopes as a function of the idiopathic or non-idiopathic presentation of TTP, the antibodies targeting the CS domains being likely the most efficient in maintaining an open ADAMTS13 conformation. 7 , 1 4 , 1 5 …”

“…However, we surprisingly observed that some rare uTTP patients (8/59, 13.6%) did have an open ADAMTS13; most of them had infections or cancer ( Figure 1E ). Several mechanisms may be hypothesized to explain these exceptional cases: 7 firstly and most likely, ADAMTS13 antibodies (either IgG trapped in ADAMTS13/IgG immune complexes or IgM/IgA class antibodies) may be present in vivo but undetectable in vitro and these cases may correspond to under- diagnosed iTTP; secondly, and less likely, hyper-elevated VWF levels, commonly observed during infections and cancers, may prolong the physiological opening of ADAMTS13; thirdly, post-translational modifications of ADAMTS13 structure induced by neutrophil-released substances during infections and inflammatory diseases (e.g., deglycosylation or citrullination/oxidation of CUB or M/S domain residues, respectively) may imbalance the stability of intra- and inter-domain interactions normally involved in the maintenance of a closed conformation. 7 These last two mechanisms remain very speculative (especially the role of hyper-elevated VWF levels) because, in the absence of any TTP context, ADAMTS13 conformation was found closed in patients with sepsis 11 or COVID-19 infection.…”