Dr Rens de Groot is a Research Fellow at the Centre for Haematology. As principal investigator, he receives funding from the British Heart Foundation, the NIH and Imperial College for studies on ADAMTS proteases and their role in cardiovascular disease.
ADAMTS13 circulates in blood and regulates the size and platelet binding capacity of von Willebrand factor (VWF). Low ADAMTS13 activity causes the life-threatening disease Thrombotic thrombocytopenic purpura (TTP). To better understand how this enzyme operates, Dr de Groot and colleagues have investigated the biochemical properties of the different domains of the enzyme and their contribution to optimal enzyme activity. A series of research projects, published in the journals Blood, PNAS and Nature Communications, revealed that the N-terminal catalytic domain is heavily dependent on exosites in three different domains. These three exosites, are positioned ~ 30, 70 and 110 ångström from the active site and bind the VWF region C-terminal of the scissile bond. In doing so, they greatly enhance the catalytic efficiency, enabling rapid proteolysis of newly secreted, ultra large VWF multimers, which would otherwise be pathogenic.
ADAMTS7 is expressed in cardiovascular tissues, where it is a component of the extracellular matrix (ECM). The enzyme became a major research interest in the cardiovascular field when genome wide association studies identified the ADAMTS7 gene as a susceptibility locus for coronary artery disease. In vivo studies subsequently confirmed expression of the enzyme in diseased or injured arteries and suggested involvement in atherosclerosis and vascular smooth muscle cell behaviour. To gain an insight in how the enzyme’s catalytic activity modifies the ECM, Dr de Groot and colleagues used a proteomic technique called Terminal Amine Isotopic Labelling of Subtrates (TAILS). This revealed that the protein latent tgf-ß binding protein 4 (LTBP4) is susceptible to proteolysis by ADAMTS7. The LTBP family members and several other ADAMTS and ADAMTS-like proteins are components of elastic fibres, which suggests that ADAMTS7 proteolytic activity may modulate elastic fibre related processes. The discovery of LTBP4 as an ADAMTS7 substrate has also enabled studies of ADAMTS7 inhibition, which have identified the protein TIMP-4 as a potent endogenous inhibitor. Development of a small molecule inhibitor is currently carried out in collaboration with Professor Armando Rossello and Dr Elisa Nuti at the University of Pisa, Italy.