1 / 19

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.

portia-benson
Download Presentation

Receptor Mechanisms

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related