Open or closed? Understanding the molecular mechanisms and clinical implications of ADAMTS13's conformation

Abstract

By proteolyzing prothrombotic von Willebrand factor (VWF) multimers, ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type-1 repeats, member 13) ensures balanced hemostasis and prevents microvascular thrombosis. ADAMTS13's conformational regulation is not only crucial for its enzymatic function, but also for the pathophysiology of thrombotic thrombocytopenic purpura (TTP). In the first part of this review, the unique structural features that keep ADAMTS13 in its closed, latent conformation are explored. Moreover, the recent structure predictions that propose a compactly folded model for closed ADAMTS13, and the molecular mechanisms involved in ADAMTS13's opening by its VWF substrate and other allosteric activators are discussed. Over the last decade, the changes in ADAMTS13's conformation in the context of immune-mediated TTP (iTTP) were increasingly characterized, with open ADAMTS13 having emerged as a novel specific biomarker for acute and subclinical iTTP. Furthermore, open ADAMTS13 is gaining clinical attention to improve the prediction of early relapses during follow-up of iTTP patients in remission. The specificity of the open ADAMTS13 biomarker for iTTP was retrospectively validated in patient cohorts with various thrombotic microangiopathies or hemostatic disorders, all dominantly presenting closed ADAMTS13. Hence, this review summarizes the molecular mechanisms that regulate ADAMTS13's conformation and links these with the clinical implications of ADAMTS13's open and closed conformations.

Figure 1

Conformational regulation of ADAMTS13's function. Two distinct structural features maintain ADAMTS13 in a latent, folded conformation in circulation. Its global latency refers to ADAMTS13's interdomain interactions that shield binding exosites for its VWF substrate. The focus inset highlights the docking of the spacer and CUB domains. The local latency reflects the structural blockade of the M domain active site. The focus inset highlights the structural occlusion of the active site by the gatekeeper triad and Ca²⁺‐binding loop. In response to allosteric co‐factors, ADAMTS13 shifts towards an active, open conformation. Non‐covalent interaction with its VWF substrate disrupts ADAMTS13's global latency uncovering binding exosites in ADAMTS13 to enable the stepwise binding to distinct VWF A2 domain regions (arrow heads). Upon local latency disruption, the Tyr¹⁶⁰⁵‐Met¹⁶⁰⁶ scissile bond is accommodated within ADAMTS13's active site for VWF A2 proteolysis. Similarly, activating antibodies (Abs) disrupt ADAMTS13's latent, folded conformation. Hereby, previously cryptic S and M domain epitopes become exposed reflecting the disruption of the global and local latency, respectively.

Figure 2

ADAMTS13 conformation during iTTP disease progression. Under healthy conditions, ADAMTS13 circulates in its closed conformation (Filled dots). During acute phase iTTP, autoantibodies trigger ADAMTS13 opening (Open dots). Upon treatment response, ADAMTS13 re‐adopts its closed conformation, whereas ongoing subclinical disease shifts ADAMTS13 towards its open conformation, which is also observed in relapsing iTTP patients. Hence, monitoring ADAMTS13 conformation during remission could support the prediction of earlier relapse risks.

Figure 3

Historical perspective on the molecular regulation of ADAMTS13 and its clinical implications. Timeline overview of the most important discoveries on the molecular regulation of ADAMTS13' conformation and function (top), and the clinical implications of open and closed ADAMTS13 (bottom).