KIT, a receptor tyrosine kinase, is dimerized at the cell surface by the cytokine stem cell factor (SCF) to initiate fundamental signalling pathways, including hematopoiesis, gametogenesis, and melanogenesis. However, recent studies have shown that KIT can also bind meteorin-like protein (METRNL) to trigger heart tissue regeneration. Ischemic heart diseases are the leading cause of mortality and morbidity worldwide. Therefore, revealing the molecular principles underlying this completely new function of KIT might open new therapeutic opportunities for maximizing post-infarction recovery. However, the field is currently plagued by a paucity of mechanistic details of the KIT.METRNL complex assembly. This project aims to derive the structure-function landscape of the novel interaction between KIT and METRNL and to provide a blueprint for how KIT can be activated by two structurally distinct ligands. The gained knowledge will govern the rational engineering of METRNL towards improving its interaction with KIT to elicit intensified signalling that can lead to amplified heart tissue regeneration. This will be achieved by synergistically combining methods of molecular and structural biology, biomolecular kinetics, rational protein engineering, and single molecule biophysics. Collectively, the project will impact basic and applied cardiovascular research and promises to provide new possibilities for alleviating the enormous socioeconomic burden associated with these diseases.