Post translational modification

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What is still required after the protein is made:
   1. Folding
   2. Proteolyric cleavage
   3. Covalent bonding
   4. Addition of other groups (phosphates, methyl groups, sugar, lipids, etc,)
   5. Translocation to the right cell compartment
Note: no all apply to all proteins and does not happen in the same order.

 Protein folding
What determines the protein structure? the primary structure? origami or spring? (manufactured or predetermined?)
Is protein structure determined by the amino acid sequence?
   YES: tertiary structure is stabilised by amino acid R groups interaction, changes in primary structure result in changes in tertiary structure, mild denaturing of proteins can be reversed
   NO: highly denatured proteins do not return to their functional native structure, in vitro (test-tube) synthesis of proteins can produce proteins with reduced or no functional activity.
  Protein synthesis and folding: Native protein: hydrophobic sequences in the protein core; non-native protein: hydrophobic areas exposed. Two main classes of protein are involved helping other proteins fold: chaperons and chaperonins
  Chaperons (e.g. heat shock proteins) are a family of proteins, work in sequence (e.g. HS 40 -> HSP70)
  Chaperonin larger structures that enclose protein; Prokaryotes: GROES, GRE; Eukaryotes: TriC/CCT.
 Process is conserved in evolution. Amyloid formation aggregation of denatured protein. Alzheimer's disease: beta amyloid plaques; Parkinson's disease: alpha-synuclein plaques.
Formation of S-S bonds: occurs predominantly in endoplasmic reticulum, sulfhydryl oxidation form 'de novo' S-S bonds. Isomerization allows swapping until 'right' confomation achieved. Cellular distribution of proteins (actin, connexin, histone, dystrophin). (Missing table of slide 17). Two major destinations after ribosome - the signal peptide: 1) cytosol, 2) organnelles or secretion. The signal peptide usually at N-terminus of protein, it is a short section of protein that determines the specific location of the protein, bind to receptor, consensus sequence (similar but not identical among proteins with same destination). Often digested after protein reaches destination.
Signal peptides:
  Destination:                            nucleus, endoplasmic reticulum, mitochondria, peroxisomes
  Location within protein:        various,    N-terminal,                 N-terminal,    C-terminal
  Consensus sequence:   lysine rich, streches of hydrophobic aa, stretches of basic aa, -Ser-Lys-Leu-COOH
 Protein translocations:
- to the nucleus: ribosome -> nuclear import receptor -> filaments, receptor complex -> nuclear pore.
- to the mitochondria: ribosome -> receptor protein -> protein translocator -> mitochondria
- to endoplasmic reticulum: ribosome -> endoplasmic reticulum -> vescicle -> golgi
(missing 25).
  Post translational proteolysis: sections of proteins are cleaved by proteolytic enzymes (e.g. signal peptides, insulin, etc.)   Preproinsulin -> proinsulin -> insulin
 Self-splicing: hedgehod protein;   (slide 30)
Addition of functional groups: (addition of) lipids, carbohydrates,   phosphorylation, ubiquitination, etc
  Addition of lipids: Facilitates protein association with membrane; different lipids target different membranes, protein anchored to membrane not spanning the membrane
 Acetylation: addition of myristoyl or palmitoyl group (e.g. G proteins). Myristoyl attached to N-terminal glycine. Palmitoyl attached to cysteine, near C-terminus
GPI anchors: glycosylphopshoinsositol: mix molecule sugar/lipids. Assembled in the endoplasmic reticulum, sugar directs protein to cell surface, can be released by phospholipases.
 Protein glycosidation: the addition of carbohydrates occurs in ER. it adds an additional ''bulk'' to the protein. Important for cell signalling: mutation lead to severe diseases.
 N-linked and O-linked glycosidation.
 Protein phosphorylation: addition of phosphate catalysed by kinase enzyme, amino acid target: Ser/Thr or Tyr (OH group), major mechanism for activation/inactivation of proteins.
 Acetylation and methylation: Acetylation:     -CH2-CO-CH3 + to Lys, Arg;    Methylation:     -CH3 + to Lys (1,2,3).
   Ubiquitination: addition of the ubiquitin peptide to other proteins (lys). Reversible process, several functions including marking protein for degradation.