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Stem cell factor (SCF) is a cytokine that mediates its diverse cellular responses by binding to and activating the receptor tyrosine kinase (RTK) KIT (also known as SCF receptor).It was initially discovered as an oncogene in a feline retrovirus. SCF functions as a noncovalent homodimer, and both membrane-anchored and soluble forms of SCF have been described.
KIT was initially discovered as an oncogene in a feline retrovirus.
SCF and KIT are required for a normal development of hematopoietic cells, melanocytes and others. In humans, loss-of-function mutations in KIT cause thepiebald trait. A variety of gain-of-function mutations in KIT were found in different types of human cancers such as gastro-intestinal-stromal tumors, acute myeloid leukemia, and mast cell leukemia.
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Structure
The two sets of KIT ectodomains and SCF molecules resemble an upside down ‘‘A’’ letter and the entire ectodomain of KIT is composed of five Ig-like domains: D1- D5. SCF dimer interacts symmetrically with D1, D2, and D3 of two corresponding KIT ectodomains. In addition, KIT ectodomains form homophylic interactions through lateral contacts between D4 and D5 of the two neighboring receptors. The folding of the 5 KIT domains is a typical folding to the immunoglobulin super family.
Structural changes upon SCF binding to Kit:
the D1-D2-D3 region of KIT might be a functional unit that is poised for SCF binding, thus leading to subsequent KIT dimerization which is driven by dimeric SCF molecules. In addition, while the overall structure of SCF bound to KIT is similar to the structure of free SCF, there are differences in the angle between the two protomers, in the conformations of the connecting loops, and in the structures of the flexible N terminus of the molecule.
The structure is also characterized by the existence of a large cavity at the center of the complex. Each protomer of SCF binds to a single KIT molecule and that receptor dimerization is driven by SCF dimers, leading to additional receptor-receptor interactions.
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Structural highlights
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