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1. Introduction
2. FGF family
3. Structure basic alignment of human FGF
4. General FGF structure
5. Why to study FGF signaling?
6. Receptor tyrosine kinase family
7. FGFR architecture
8. Alternative splicing (AS)
9. Tissue specific alternative splicing in FGFR1-3
10. FGF require proteoglycans
11. Structural biology of FGFR activation
12. Questions to be answered
13. Crystal structure of FGFR complex/FGF/heparin
14. Space filling of the dimer
15. The dimerization of FGFR
16. The role of heparin sulfate (HP) in FGFR
17. Heparin-binding canyon
18. Interaction between HP and ligand or receptors
19. Interactions of heparin with FGFR
20. A dynamic model for generation of dimers (1)
21. A dynamic model for generation of dimers (2)
22. A dynamic model for generation of dimers (3)
23. FGF-FGFR dimerization is cooperative process
24. Different canyons of HS motifs
25. FGFR autoinhibition
26. D1 and the D1-D2 linker interact with D2-D3
27. Molecular basis for FGF-FGFR binding specificity
28. Summary of FGF-FGFR binding data
29. Structure - summary
30. AS in FGFR1-3 and ligand binding specificity
31. FGF2 binds to receptor 2C
32. FGF2-D3 interface
33. FGF10 binds to FGFR2B
34. FGF10-D3 interface
35. Site directed mutagenesis experiments
36. AS regulates tissue homeostasis-structural basis
37. AS generates multiple FGF8 isoforms
38. AS modulates the organizer activity of FGF8 (1)
39. AS modulates the organizer activity of FGF8 (2)
40. Crystal structure of FGF8b with FGFR2c
41. Higher binding affinity accounts for a single residue
42. Mutation reduces FGFR binding affinity of FGF8b
43. Differences in patterning abilities of FGF8a/FGF8b
44. Take home message
45. FGF8b attains differently its binding specificity
46. The unique conformation of FGF8b N-terminus
47. Mechanisms of FGF-FGFR binding specificity
48. D3 superimposition
49. Divergent N-termini of FGF and regulation
50. The conformation of FGF N-terminus differs greatly
51. Structural basis for FGFR activation in disease
52. Positions of various mutations
53. Location of a specific mutation leads to disease
54. Apert syndrome
55. Crystal structure of wt and mutant receptor 2c
56. Gain-of-function contacts (1)
57. The superimposition of wild type FGFR2c
58. Gain-of-function contacts (2)
59. Apert mutations enhance the affinity
60. FGF10 binds the mutant receptor
61. Loss of FGFR2 binding specificity
62. Pfeiffer syndrome
63. Pfeiffer syndrome - FGFR2 A172F mutation
64. The FGFR2 mutation
65. Acknowledgments

Topics Covered

• FGF family of ligands, and FGF receptor (FGFR) subfamily of receptor tyrosine kinase superfamily
• The roles of FGF signaling in mammalian biology and diseases
• FGFR receptor alternative splicing and its essential role in epithelial-mesenchymal signaling loop, and organogenesis
• Structural mechanism by which FGF and heparan sulfate induce FGFR dimerization and activation on the cell surface
• A working model for FGFR autoinhibition
• Structural mechanisms by which FGF-FGFR binding specificity is achieved
• Structural basis for how alternative splicing regulates ligand-binding specificity of FGFRs
• Structural basis by which ligand-dependent pathogenic mutations in FGFR lead to receptor gain-of-function in human skeletal syndromes
• Structural basis by which alternative splicing regulates patterning ability of FGF8 in the brain

Links

Series:

• Signal Transduction via Protein Tyrosine Kinase Receptors

Categories:

• Biochemistry
• Cell Biology

Talk Citation

Mohammadi, M. (2007, October 1). Structural biology of FGF signaling in human development and disease [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 21, 2024, from https://doi.org/10.69645/ZDNT1040.
Export Citation (RIS)

Publication History

• Published on October 1, 2007
• Archived on December 10, 2018

Financial Disclosures

• Dr. Moosa Mohammadi has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.