Protein modules PTB domains: 100-150 aa. bind to in npxy motifs shc IRS-1 PDZ domains: -80-90 aa, recognize short peptide motifs (4-5 residues) at the C-terminus of membrane proteins. usuall containing a hydrophobic residue at the very end; protein-protein interaction Dishevelled, FAP SH2 (src homology) -100 aa, binds to phosphotyrosine residues: Src, Grb2 ShC. STAT SH3: binds to proline-rich sequences(PXXP): Src, Nck WW domains: bind to Pro-rich sequences (XPPXY: Nedd4(E3 ubiquitin ligase), Smurf, Dystrophin Death domains: Fas LIM domains: recognize turn-based motifs PH(Pleckstrin-homology) domains: associate with phosphinositides (P13, 4P2; P14, 5P2: P13, 4, 5P3), target proteins to the plasma membrane: Akt. SOS FYVE domains: associate with phosphinositides(P13P), target proteins to endosomes: EEAl, SARA There are about 115 SH2 and 253 Sh3 domains encoded by the human genome
3)Four general types of signal transducers (a)G protein-coupled receptors (epinephrine, glucagon, serotonin) Exterior Ligand. Plasma membrane 单回一岛 →E Cytosol Receptor Inactive G Inactive effector Activated Active effector protein signal enzyme (adenylyl form of generates"second transducing cyclase, phospho- G protein messengers"(cAMP; protein lipase c, or others) inositol 1,4,5 phoshate 1, 2-diacylglycerol) (b)lon- channel receptors(acetylcholine Ligand Ligand binding-site Exterior Cytosol Receptor prote
(3) Four general types of signal transducers
(c) Tyrosine kinase-linked receptors(erythropoietin, interferons Ligand◆ A ADP ATP ATP Phosphorylated substrate protein HO Protein-tyrosine kinase (inactive) Substrate protein (d) Receptors with intrinsic enzymatic activity Ligand● Ligand■ Exterior Cytosol GTP 3. 5'-cyclic GMP A Tyrosine kinase Guanylate cyclase activity activity (nerve ADP (atrial naturetic factor growth factor, ADP platelet-derived growth factor) ATP
C. Two types of intracellular signaling proteins that act as Molecular Switches SIGNAL IN SIGNAL IN GEF: guanine nucleotide- GPPI exchange factor APPP OFF GPP OFF GRF: guanine P ON GPP P ON nucleotide release factor GAP: GTPase LGPPP SIGNAL OUT SIGNAL OUT activating protein A) SIGNALING BY PHOSPHORYLATION (B) SIGNALING BY GTP-BINDING PROTEIN o Phosphorylation and dephosphorylation%GAPs inactivate G-protein; GEFS via protein kinases and phosphatases activates G-protein; GDIs(guanine Thereby stimulating or inhibiting the nucleotide-dissociation inhibitors activities maintain the G-protein inactive
C. Two types of intracellular signaling proteins that act as Molecular Switches. ❖Phosphorylation and dephosphorylation via protein kinases and phosphatases. Thereby stimulating or inhibiting the activities ❖GAPs inactivate G-protein; GEFs activates G-protein; GDIs(guanine nucleotide-dissociation inhibitors) maintain the G-protein inactive. GEF:guaninenucleotideexchange factor GRF:guaninenucleotide release factor, GAP:GTPaseactivating protein
The Nobel Prize in Physiology or Medicine 1992 "for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism Edwin G. Krebs Edmond H. Fischer Protein kinase TP ADP Protein phosphatase P
The Nobel Prize in Physiology or Medicine 1992 “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism