Intracellular Traffic and Sorting of Proteins
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The document discusses the mechanisms of intracellular traffic and sorting of proteins, focusing on protein targeting, quality control, and degradation in various organelles like the endoplasmic reticulum, Golgi apparatus, and lysosomes. It also highlights key processes like vesicle transport, the role of signal peptides and sequences in targeting, and clinical conditions arising from defects in these mechanisms. Additionally, it covers the significance of peroxisomal and mitochondrial targeting signals in the import and degradation of proteins.
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• R or v-SNARE
Synaptobrevin
• Q or t-SNARE
Syntaxin
SNAP-25 [Synaptosome
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SNARE
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Intracellular Traffic and Sorting of Proteins
- 1. Intracellular Traffic & Sorting of Proteins Ashikh Seethy JuniorResident Dept ofBiochemistry MAMC– New Delhi
- 3. Ribosomes:
- 6. Overview: • How proteins are targeted to their correct destinations? • Clinical conditions associated with defects in protein targeting • Drugs • Mechanisms of certain toxins • Maintenance of quality control in protein traffic • Vesicle transport • Degradation of proteins in proteasomes
- 7. A majorsorting decision is made earlyduring protein synthesis
- 9. Gunter Blobel • There is no difference between structure of free and bound ribosomes • Selection of mRNA to the ER membrane is not via direct binding of the mRNA itself, but rather via binding of its nascent translation product • Signal hypothesis
- 10. Signal peptide enables the binding of ‘bound ribosome’ -TheSignal Hypothesis • N-terminal • 13-36 residues • 6-15 hydrophobic core flanked by hydrophilic residues • 1 or 2 basic residues near the N-terminal • Small and neutral residues near the cleavage site
- 13. Type I Transmembrane Protein
- 14. Type II, III & IV Transmembrane Proteins
- 17. Quality Control in Endoplasmic Reticulum-ERAD
- 19. Unfolded Protein Response and DM
- 20. From ER to Golgi and Further
- 22. Coat proteins Golgi>>>PM/Lysosomes ER>>>Golgi Golgi>>>ER
- 23. Fusion • R or v-SNARE Synaptobrevin • Q or t-SNARE Syntaxin SNAP-25 [Synaptosome Associated Protein] • Disassembly: SNARE SNAP NSF
- 24. Fusion
- 25. Vesicletransport
- 26. ER resident proteins havea KDEL sequence • C-terminal: KDEL KKXX KXKXXX • "If found, please return to ER"
- 28. I-cell disease • Mucolipidosis II • UDP-N -acetyl glucosamine phosphotransferase • Cultured fibroblasts-deficient in numerous lysosomal enzymes • Inclusions in lysosome • These enzymes were found to be present in excess in tissue culture media and in extracellular fluids • Psychomotor and skeletal defects
- 29. Cytosolicpathway
- 30. Proteinimport to peroxisomes: • Peroxisomal matrix targeting sequences • PTS-1: SKL • PTS-2: N-terminal (R/K)(L/V/I)X5(H/Q) (L/A)
- 31. The Zellweger spectrum: • Zellweger cerebrohepatorenal syndrome • Neonatal adrenoleukodystrophy • Infantile Refsum disease • Peroxisomal biogenesis disorders • Mutation in PEX genes Impaired plasmalogen synthesis Impaired very long chain fatty acid (VLCFA) beta oxidation Impaired alpha oxidation
- 32. Signal sequences for nuclear import are not cleaved • Nuclear Localisation Signal – Pro-Pro-Lys-Lys-Lys-Arg-Lys-Val
- 34. Protein degradation • 76 residues • Highly conserved • Isopeptide bonds Juvenile onset Parkinsonism HPV • 26 S proteasome 20S core subunit 19S regulatory subunit • Bortezomib and Carfilzomib
- 35. Summary
- 36. Than k
Editor's Notes
- #4: Only organelle in prokaryotes NP-1974 Ribosome and ER
- #6: Free and bound ribosomes are structurally similar
- #15: Positive inside rule
- #16: None consensus sequence characterizes the amino acid at the ω-site (69). Some residues experimentally verified in ω-site include: cysteine, aspartic acid, glycine, asparagine, and serine (69). However, some generally features can be found in the non-cleaved C-terminal end of glypiated proteins like: an unfolded linker region comprising about 11 residues (upstream from position ω-1), a region comprised by small amino acids surrounding the cleavage site (from positions ω-1 to ω+2) which is followed by a moderately polar spacer region (from positions ω+3 to ω+9) and finally, a hydrophobic tail extended from the position ω+10 up to the C-terminal end
- #18: ER degradation-enhancing α-mannosidase; Dislocon; Isomers of mannose
- #21: Congenital disorder of glycosylation
- #24: Worlds most potent toxin
- #25: Time taken
- #29: MPS and sphingolipids
- #31: PEX-peroxins
- #32: AR; Plasmalogen- myelin