SCF-KIT: Difference between revisions
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<StructureSection load='2E9W' size='340' side='right' caption=' | <StructureSection load='2E9W' size='340' side='right' caption='Glycosylated Kit tyrosine kinase (pink, yellow) complex with stem cell growth factor receptor (grey, green) (PDB code [[2e9w]])' scene='> | ||
== Introduction == | == Introduction == | ||
'''Stem cell factor (SCF)''' is a cytokine that mediates its diverse cellular responses by binding to and activating the [https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase (RTK)]. [https://en.wikipedia.org/wiki/CD117 KIT] (also known as [https://en.wikipedia.org/wiki/Stem_cell_factor SCF]receptor), functions as a noncovalent homodimer, and both membrane-anchored and soluble forms of SCF have been described. | '''Stem cell factor (SCF)''' is a cytokine that mediates its diverse cellular responses by binding to and activating the [https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase (RTK)]. [https://en.wikipedia.org/wiki/CD117 KIT] (also known as [https://en.wikipedia.org/wiki/Stem_cell_factor SCF]receptor), functions as a noncovalent homodimer, and both membrane-anchored and soluble forms of SCF have been described. | ||
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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-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. | 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 [https://en.wikipedia.org/wiki/Immunoglobulin_domain 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. | ||
[[image:5domain.jpg | thumb | 150px | center | Five | [[image:5domain.jpg | thumb | 150px | center | Five Ig-like domains of KIT]] | ||
'''Structural changes upon SCF binding to KIT:''' | '''Structural changes upon SCF binding to KIT:''' | ||
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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 [https://en.wikipedia.org/wiki/Autophosphorylation 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 cell-surface 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 occurs 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. Since the hallmarks of KIT structure, ligand binding and receptor dimerization are conserved in other receptors, it is believed that the mechanism described above for KIT activation is 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 [https://en.wikipedia.org/wiki/Autophosphorylation 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 cell-surface 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 occurs 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. Since the hallmarks of KIT structure, ligand binding and receptor dimerization are conserved in other receptors, it is believed that the mechanism described above for KIT activation is a general mechanism for activation of many receptors. | ||
== 3D structure of SCF == | |||
See [[Tyrosine kinase]] | |||
== References == | == References == | ||