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Protein: Post-translational Modification 林富邦老師 Gene encoding region (ORF) ↓transcription mRNA ↓translation Protein (nascent protein, precursor protein) ↓protein processing, post-translational modification Mature protein ↓folding Biological active protein Post-translational Modification 1. numerous and diverse 2. change the charge, conformation or size of protein molecule Effects of Post-translational Modification 1. stability of protein 2. biochemical activity (activity regulation) 3. protein targeting (protein localization) 4. protein signaling (protein-protein interaction,cascade amplification) Why protein post-translational modifications are made? (Biological functions) A. Regulation (interconvertable modifications) Monocyclic cascade (allosteric effectors) -P/de-P receptor-associated Tyr-Kinase coupled cascade Cyclic cascade ADP-ribosylation / poly-ADP-ribosylation Coordinated Glycogen phosphorylase / Glycogen synthase Unidirectional cascade Proteolytic activation B. Cross-links Stabilize or fix certain folded str. (Cofactors covalent binding) Disulfide bond-cross links (Cys-Cys) Isopeptide (N-(γ-Gln)-Lys Transamidation (Gln→Lys or Ornithine-α-NH2) (Transglutaminases) Blood clotting factor VIII – coagulation Tissue Transglutaminase reaction Cell proliferation, aging, endocytosis, secretion, differentiation, apotosis, programmed cell death C. Covalent Cofactors Biotinyl lysine (Carboxylase, transcarboxylases) Cys-bound linear tetrapyrrole (phycobiliproteins lightharvesting system of photosynthetic microorganisms) FAD-linked His, Cys, or Tyr (DHase, Oxidase) FMN-linked Cys Heme-covalent bound (Cyt. C) D. Membrane Anchors α-NH2 myristoyl Cys- fattyacyl thioether Ser- palmitate or other fatty acids esters Thr- C-terminal glycophospholipids C-terminal Cys – prenylated group Farnesyl C15, Geranylgeranyl C20 E. Signaling, Recognition and Structural Amplification F. Protein Turnover (Protein Degradation) Spontaneous Oxidation: Cys, His, Tyr, Met Ubiquitination: Lys G. Others Iodination: Tyr, (Thyroid hormones) Sulfation or methylation; Tyr / secreted proteins Types of Post-translational Modification A. Modification Involving Peptide Bonds Cleavage (limited proteolysis) 1. Peptide Bonds Cleavage (limited proteolysis, specific and well-regulated ) Signal leader peptide removed by signal peptidase (both in prokaryotes and eukaryotes) Precursor protein → mature protein (Insulin) Zymogen → active enzyme Trypsinogen → Trypsin Pepsinogen → Pepsin Prohormone → Hormone Polyprotein → neuropeptides (peptide hormone ) conversion 2. Peptide Bond Isomerization (Intramolecular) Ser → esters Cys → thioesters Asp or Asn → isoaspartate Prolyl peptide cis-trans isomerization (prolyl isomerase catalyzed) 3. Peptide Bond Formation, Transpeptidation peptide bond splicing with peptide deletion and/or permutation Plant lectin – Concanvalin A B. Modifications Involving Amino and Carboxyl Termini 1. The N terminus:H3N+— N-Formyl- (C1) N-Acetyl- (C2) N-Acyl- (C2, C4, C6, C8, C10) N-Lauroyl- (C12) N-Myristoyl- (C14) N-Tetradeca (mono and di)enoyl- (C14:1; C14:2) N-AminoacylN-α-KetoacylN-MethylN-Pyrrolidone carboxylN-GlucuronylN-Glycosyl- 2. The C Terminus: Amide O-(ADP-ribosyl)O-Methyl-(N-Ethanolamine-glycan-phosphoinositides) -(Nα-TyT) C. Modifications Involving Individual Amino Acid (Side Chains) 1. Arginine: Nω-(ADP-ribosyl)Nω-MethylNω-DimethylNω-Nω’-Dimethyl- Ornithine Citrulline Nω-Phosphoryl- 2. Asparagine: N-GlycosylAspartate N-Methyl- Nε-(β-Aspartyl)lysine erythro-β-HydroxyN-(ADP-ribosyl)- 3. Aspartate: D-Asp (racemization) β-Carboxyerythro-β-Hydroxy- β-MethylthioO-PhosphorylO-Methyl- 4. Cysteine:HS-CH2 Cystine S-γ-GlutamylS-(2-Histidyl)S-(3-Tyr) S-(sn-1-Glyceryl)S-(sn-1-Diacylglyceryl)S-(sn-1-{2,3,-Di-O-[3’ ,7’ ,11’ .15’tetramethylhexadecyl]}glyceryl)S-PalmitoylS-FarnesylS-GeranylgeranylS-Heme S-Phycocyanobilin S-p-Coumaroyl S-(6-Flavin [FMN]) S-(8α-Flavin [FAD]) S-Coenzyme A S-(ADP-ribosyl)S-GlycosylDehydroalanine Lysinoalanine Lanthionine Selenocysteine 5. Glutamate: O-(ADP-ribosyl) γ-CarboxyO-MethylNα-(γ-Glutamyl)-Glu1-5 Nα-(γ-Glutamyl)-Glu3-34 N- (γ-Glutamyl)ethanolaminephosphate) S-γ-Glutamyl-Cys is listed under Cys 6. Glutamine: Glutamate Nε-(γ-Glutamyl)lysine N-(γ-Glutamyl)-L-ornithine N-(γ-Glutamyl)polyamine N,N-(Bis-γ-glutamyl)polyamine N5-Methyl- 7. Histidine: Diphthamide Nτ-(ADP-ribosyl)diphthamide N-PhosphorylNπ-Methyl4-Iodo-and diiodoNτ- and Nπ –(8α-flavin [FAD]) Nπ-(8α-Flavin[FMN]) 8. Lysine: Nε-AcetylNε-( Nα-Monomethylalanyl)Nε-Murein (peptidoglycan) Nε-LipoylNε-BiotinylNε-UbiquitinylNε-PhosphorylNε-PhosphopyridoxylNε-Retinyl- Nε-GlycosylNε-Mono-, di- , trimethylHypusine:Nε-(4-amino-2-hydroxybutyl)Allysine δ-Hydroxyδ-Hydroxyallysine Cross-links (desmosines, syndesines, pyridinolines) δ-Glyxosyloxy- 9. Methionine: Sulfoxide 10. Phenylalanine: β-Glycosyloxy- 11. Proline: 3-Hydroxy4-Hydroxy3,4-DihydroxyO4-ArabinosylhydroxyO4-GalactosylhydroxyO4-Glucosylhydroxy- 12. Serine:HO-CH2 Selenocysteine O-PhosphorylO-PantetheinephosphorylO-(GlcNAc-1-phosphoryl)O-(Glycerol-1-phosphoryl)O-Methyl- O-GlycosylAlanino(τ- or π-histidine) Lanthionine O-AcetylO-Fatty acyl- How modifications are made ? A. Nonenzymatic Reaction deamidation:Asn, Gln racemization:Asp, Ser dehydroalanine:Cys, phosphor-Ser slow oxidation:Cys, His, Met slow cleavage and permutation of peptide bonds reducing sugar reaction with NH2-group of aa’s or side chains (Lys):Maillard reaction (Browing reaction); Schiffs base reaction. B. Enzymatic Reaction 1. Irrversible, Unidirectional Reaction (permanently modified) N-linked glycosylation Carboxyl methylation S-isoprenylation-Cys 2. Irrversible, Bi-directional Reaction. (Signal Amplificaion) Phosphorylation (protein kinase) / Dephosphorylation (phosphatase):Ser, Tyr, Thr. Uridylyl and adenylyl transfer in bacterial glutamine synthetase 3. Reversible Reaction RS-SR + R’-SH ↹ R’-S-S-R + RSH(disulfide isomerase) Coupled with protein-folding process