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Receptor Mechanisms

Receptor Mechanisms. General Mechanisms Transmit information through membrane Conformational change Active state Aggregation Inactivation Cytoplasmic effects Examples. Ligand Binding. Membrane. Biologically Active. Communication.

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Receptor Mechanisms

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  1. Receptor Mechanisms • General Mechanisms • Transmit information through membrane • Conformational change • Active state • Aggregation • Inactivation • Cytoplasmic effects • Examples LigandBinding Membrane Biologically Active

  2. Communication • Transmit information from one side of membrane to the other • Transmembrane, allosterically regulated proteins • Amplification • Adaptation (negative feedback) • Receptor internalization • Antagonistic cascade activation

  3. Sources of information • External environment • Ions • Nutrients • Matrix • Cell-cell signals • Autocrine – cell to itself or its sisters • Paracrine – cell to its neighbors • Neurotransmitters • Endocrine – cell to anyone in shouting distance

  4. Receptor ligation induces conformational change • Single transmembrane domain • Ligand mediated dimer-/oligomer-ization • Oligomer remodeling Extracellular domain of FGF2 receptor with FGF PDB:1e0o

  5. Caveats inferring from crystal structures PDB:1e0o Cytoplasmic domain? PDB:1ev2 Higher order symmetry?

  6. Ligand mediated conformational change • Extracellular polymerization • Cytoplasmic assembly • Kinase • Phosphatase • G-cyclase • Adapter domain • 7-pass receptors • GEF activation • Signal amplification

  7. Negative feedback • Effector inactivation • Antagonists – PI3K/PTEN • Inhibitors –GRKs • Receptor internalization • Clathrin coated pits • Caveolae

  8. Clathrin mediated internalization • Recruitment of adapters • PIP3, Grb2, Cbl • AP2/b-arrestin • Assembly of clathrin shell • Collar constriction • Dynamin • actin Fig 22-9

  9. Caveolae mediated internalization • Caveolae are constitutive • Signaling platforms due tospecial composition • Ligated receptors activateRho GEFs • Actin remodeling • Dynamin • Membrane fission • Retrograde microtubule transport

  10. Endosomal sorting • Proteasome/lysosome mediated degradation • Trans-Golgi network recycling • Ligand and receptor specific • Ubiquitin caveola Clathrin- coated vesicle caveola Trans-Golgi Sorting Endosome Endosome Lysosome X

  11. Receptor families • ID by cytoplasmic homology • Functions • Kinases • Tyrosine • Serine/Threonine • Phosphatases • GEFs • Guanylate cyclase • Anchorage • Ion transport

  12. Receptor tyrosine kinases (RTKs) • Canonical growth factor receptor • Ligand induces dimerization • Autophosphorylation • Substrate phosphorylation • Complex formation • Diverse ligands FGF FGF Yet a 3rd structure for FGF-FGFR Membrane

  13. Serine/Threonine kinases • Heterodimeric • Ligation induced tetramerization • Phosphorylate SMADs • Small Mothers Against Decapentaplegic • Transcription factors • Ligate Transforming Growth Factors (TGFs) Top view TGFbR-2 -1 TGFb Groppe et al., 2008

  14. Cytokine receptor • Lack intrinsic activity • Signaling through JAK/STAT • Tyrosine kinase • Receptor+JAK is functionally equivalent to RTK • Ligate interleukins, interferons, GH Top Side IL6Rb IL6 IL6Ra PDB: 1p9m

  15. TNF Receptors • Trimeric • Sphingomyelinase • Ligates TNFs, FAS TNF receptor Trimeric TNF PDB: 1tnr

  16. Integrin • Heterodimer • Lack intrinsic activity • Coordinate intracellular and extracellular assembly • Ligate ECM • Mechanoactive Closed Open Ligated Xiao et al., 2004

  17. Cadherin • Calcium-mediated trans-dimerization • Cell-Cell Adhesion • b-catenin, a-catenin, cytoskeleton E-cadherin Cell 1 Cell 2 Cell 2 b-catenin Cell 1 a-catenin PDB: 1q5b PDB: 1q55 PDB: 1l3w,1l7c, 1i7w

  18. G-Protein Coupled Receptor • GPCR are 7 pass transmembrane proteins • Rhodopsin/b-adrenergic • Secretin/vasointestinal peptide • Metabotropic glutamate • Ga Guanine exchange factor (GEF) • Heterotrimeric G-Protein • Ga - Gbg binding

  19. GPCR • Receptor ligation catalyzes GDP-GTP exchange on Ga • GTP bound Ga dissociates from Gbg • Ga modulates secondary signaling • Gbg may also modulate secondary signaling Receptor Bound Receptor Ga-GDP Ga-GTP Gbg Gbg

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