Aberrant Signal (autoimmune-thyropathy)StimulatoryAbBlocking AbTSH-R30~35aaresiduesGsGqTSH-R295~302385~395ACPLCAAresiduesDGIPCAMP1Binding of TSH to RJPKC美1Thyroid proliferation & secretion hypothyroidismhyperthyroidism
Binding of TSH to R↓ hypothyroidism Aberrant Signal (autoimmune-thyropathy) Blocking Ab TSH-R 295~302 385~395 AA residues Gs AC cAMP Thyroid proliferation & secretion Gq PLC IP3 DG Ca2+ PKC TSH-R 30~35aa residues Stimulatory Ab hyperthyroidism
2. Aberrant Receptor in CellSignaling? Receptor gene mutation?Receptor down regulation ordesensitization
2. Aberrant Receptor in Cell Signaling • Receptor gene mutation • Receptor down regulation or desensitization
Receptor Gene Mutation Genetic insulin-resistant diabetesIR gene mutationsInsulin+RActivate RPTKDisturbancesin synthesisIRSin transfer to the membranein affinity to insulinPI3KRas/Raf/MEKERKin RPTKactivationGlycogenin proteolysisCellSynthesis,+TransportproliferationType II Diabetes&Utilization
Receptor Gene Mutation — Genetic insulin-resistant diabetes IR gene mutations Disturbances in synthesis in transfer to the membrane in affinity to insulin in RPTK activation in proteolysis Type II Diabetes Insulin+R Activate RPTK IRS PI3K Ras/Raf/ MEK/ERK Glycogen Synthesis, Cell Transport proliferation & Utilization
Response oftheinsulinreceptorkinase(IRK) to ligand bindingInsulin-binding siteHeterotetramer (2α,2)Insulin bindingleads toMembranechangein structureTyrosinekinasedomainConformation changeC-terminaltaiIRSactivates β-subunitTKactivityβ-subunitphosphorylatesMembraneTyr residues oncytoplasmic domains asPhosphategroupsPPP00ePPwell as downstream?Osubstrates (IRS)IRSP
Response of the insulin receptor kinase (IRK) to ligand binding ◼ Heterotetramer (2, 2) ◼ Insulin binding leads to change in structure ◼ Conformation change activates -subunit TK activity ◼ -subunit phosphorylates Tyr residues on cytoplasmic domains as well as downstream substrates (IRS)
Lhree-dimensionastructuresoftheinsulinreceptor tyrosinekinase (IRK)IRKconformationalchangeuponactivationloopphosphorylation.TheNterminallobeofIRKiscoloredwhiteandtheC-terminallobeiscoloreddarkgrey.Theactivationloop (green)containsautophosphorylationsitesY1158.Y1162andY1163.andthecatalyticloop(orange)containstheputativecatalyticbase,D1132.Alsoshown arethe unbound/boundATPanalogand tyrosine-containingsubstratepeptide (pink).[Hubbard,EMBO J.16,5572(1997))
Three-dimensional structures of the insulin receptor tyrosine kinase (IRK) IRK conformational change upon activation loop phosphorylation. The Nterminal lobe of IRK is colored white and the C-terminal lobe is colored dark grey. The activation loop (green) contains autophosphorylation sites Y1158, Y1162 and Y1163, and the catalytic loop (orange) contains the putative catalytic base, D1132. Also shown are the unbound/bound ATP analog and tyrosine-containing substrate peptide (pink). [Hubbard, EMBO J. 16, 5572 (1997)]