Thesis Boğaç Erçığ

Summary

Thrombotic thrombocytopenic purpura is a rare, life-threatening disease which is portrayed by profound thrombocytopenia, microangiopathic hemolytic anemia and severe organ failures. TTP is classified as a thrombotic microangiopathy (TMA), and only ADAMTS13 deficiency distinguishes TTP from the rest of TMAs. ADAMTS13 deficiency is rarely caused by mutations in the ADAMTS13 gene (congenital TTP; cTTP) or commonly due to the development of anti-ADAMTS13 autoantibodies (immune-mediated TTP; iTTP). 
The main focus of this thesis is to improve the understanding on the structure and function of ADAMTS13 which provides novel insights on how the enzyme performs at molecular level to maintain hemostasis and to design novel therapeutic options for iTTP patients. In overall, we established a structure and the function relationship for ADAMTS13 and discovered the effects of cTTP causing mutations on ADAMTS13 structure. Additionally, we succeeded to generate novel ADAMTS13 spacer mutants which were able to resist against the autoantibodies while maintaining proteolytic activity. Next, we further observed the conformational changes of ADAMTS13 to better explain the interplay with its substrate VWF. Furthermore, we shared our strategic insights to modulate the protein-protein interactions and gave an example of how these strategies can be applied in the concept of TTP where the VWF and platelet interactions can be inhibited by structure-based design of a peptide inhibitor to prevent thrombocytopenia.  
In conclusion, our studies on the structure and function relationship of ADAMTS13 provided several insights to tackle the unmet needs of iTTP patients and they hold a significant potential to be included in the therapeutic arsenal of iTTP treatment.