SCF-KIT: Difference between revisions
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== Structure == | == 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<Structure load='2E9W' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | 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. <Structure load='2E9W' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> 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:''' | '''Structural changes upon SCF binding to KIT:''' | ||
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Dimerization of KIT is also mediated by homotypic interactions between the two membrane-proximal Ig-like domains of KIT, namely by D4-D4 and D5-D5 interactions. This results in a significant change in the configurations of D4 and D5 relative to the rest of the molecule. These configurations bring the C termini of the two neighboring ectodomains within 15 A° of each other close to the place where they connect to the transmembrane domain. | Dimerization of KIT is also mediated by homotypic interactions between the two membrane-proximal Ig-like domains of KIT, namely by D4-D4 and D5-D5 interactions. This results in a significant change in the configurations of D4 and D5 relative to the rest of the molecule. These configurations bring the C termini of the two neighboring ectodomains within 15 A° of each other close to the place where they connect to the transmembrane domain. | ||
SCF-KIT interface can be divided to three: siteI, site II and site III. | SCF-KIT interface can be divided to three: siteI, site II and site III. | ||
The dimerization of KIT is made possible by <scene name='70/702908/Scf_bound_to_kit/1'> | The dimerization of KIT is made possible by <scene name='70/702908/Scf_bound_to_kit/1'>bivalent SCF binding</scene> whose sole function is to bind SCF and to bring together two KIT molecules. This dimerization is followed by a large change in D4 and D5 orientations relative. It was proposed that the flexible joints at the D3-D4 and D4-D5 interfaces enable lateral interactions that result in a large conformational change upon receptor dimerization. In the process of dimerization there is a selection between particular conformations in a transition from a flexibly jointed monomer to a rigid dimer. | ||
A similar mechanism was found in VEGFR, vascular endothelial growth factor receptor. | A similar mechanism was found in VEGFR, vascular endothelial growth factor receptor. | ||
VEGFR takes part in regulation of blood and lymphatic vessel development and homeostasis. | VEGFR takes part in regulation of blood and lymphatic vessel development and homeostasis. | ||
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== Mutations == | == Mutations == | ||
Mutations: | Mutations: | ||
A point mutation in either Arg381 or Glu386 within D4 can strongly compromise SCF-induced tyrosine autophosphorylation. The homotypic interactions between membrane-proximal regions of KIT are mediated primarily by the D4-D4 interface, while the D5-D5 interface plays a cooperative secondary role, i.e., the D5-D5 faciliates the exact positioning of two KIT ectodomains at the cellsurface interface. SCF-KIT binding occurs in at least two steps: first, the electrostatic attraction between SCF and D1-D2-D3 will align SCF along the opposing ligand-binding region on KIT. A faster association rate might occur as a result of an electrostatic attraction of SCF due to a steering effect. Interestingly, the main interactions that maintain the D4-D4 interface, i.e. double salt bridges between Arg381 and Glu386 in a neighboring KIT molecule are also mediated by electrostatic interactions. Cell-cell interactions, the ectodomain of KIT has evolved since the hallmarks of KIT structure, ligand binding, and receptor dimerization are conserved in other receptors, the mechanism described above for KIT activation may be a general mechanism for activation of many receptors. | A point mutation in either <scene name='70/702908/R381_and_e386/1'>Arg381 (green) or Glu386 (magenta)</scene> \ within D4 can strongly compromise SCF-induced tyrosine autophosphorylation. The homotypic interactions between membrane-proximal regions of KIT are mediated primarily by the D4-D4 interface, while the D5-D5 interface plays a cooperative secondary role, i.e., the D5-D5 faciliates the exact positioning of two KIT ectodomains at the cellsurface interface. SCF-KIT binding occurs in at least two steps: first, the electrostatic attraction between SCF and D1-D2-D3 will align SCF along the opposing ligand-binding region on KIT. A faster association rate might occur as a result of an electrostatic attraction of SCF due to a steering effect. Interestingly, the main interactions that maintain the D4-D4 interface, i.e. double salt bridges between Arg381 and Glu386 in a neighboring KIT molecule are also mediated by electrostatic interactions. Cell-cell interactions, the ectodomain of KIT has evolved since the hallmarks of KIT structure, ligand binding, and receptor dimerization are conserved in other receptors, the mechanism described above for KIT activation may be a general mechanism for activation of many receptors. | ||
</StructureSection> | </StructureSection> | ||