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Signalling Protein (Signaling Modules (SH3 domain (polyproline type-II…

- - - - Interaction between PPII and SH3
        
        good sticky arms (flexible linker + rigid sections) + electrostatics attraction (Arg on the peptide)
        
        The PXXP motif fits into the grooves and bumps of the SH3 domain surface (formed by aromatic residues) #
        
        The PPII helix wraps around the 3-10 helix
      - The arginine side chain (on PPII ligand) is flexible and can accommodate slight change in backbone position.
      - Class I: RXXPXXP; Class II: PXXPXR
    - - HIV Nef: additional pocket on Nef core domain also interacts (hydrophobic) with the RT loop on SH3.
      - Herpes virus TIP: additional conserved LG residue of TIP (next to the PXXP motif) binds to the hydrophobic pocket on SH3
- - - - Homogeneous (not a mixture of different state)
      - Well-dispersed (not aggregated or denatured)
      - Randomly orientated
  - - - detector technology improve allow to take many image with short exposure, less movement
      - image processing improvement allows to process a large amount of image
- - - - linker holds the Trp in the right orientation to interact with the hydrophobic residue
      - linker holds the C-helix such that salt bridge cannot form.
    - - C-helix changes its position and form salt bridge with the critical lysine such that ATP can be positioned in the right orientation.
    - - phosphorylation of the tail (inactivating)
        
        phosphorylated C-terminal tail(pTyr) bound to SH2 domain #
      - phosphorylation of the protein kinase domain (activating) #
      - contacts between (SH2 + C-lobe) and (SH3 + N-lobe) stabilizes helix-C in its inactive position, the salt bridge is broken #
        
        disrupt the contacts can activate Src (both SH2 and SH3 ligand is activating)
        
        Break the SH2 +C-tail contacts (pYEEI competing with phosphorylated C-tail)
        
        Break the SH3 + N-lobe contacts between (binding to HIV Nef)
  - - - salt bridge forming between acidic residue on PSTAIRE helix and basic residue in the active site.
      - K33 from cyclin position ATP in a correct orientation
  - - - Residue (Thr,Ser,Tyr; on the activation loop in the C-lobe) bound into the active site
      - stabilise the inactive helix-C position and prevent real substrate getting in
    - - residue is excluded from the active site
      - activation loop is fixed preventing helix-C from returning to the off position
- - - - 4-helix bundle (Up-Up-Down-Down)
      - extra helices in AB and CD loop
    - - promotes growth of bone, cartilage, and soft tissues (mediated by IGF-1)
      - Overproduction: acromegaly (gigantism)
      - Underproduction: panhypopituitarism (pituitary dwarfism)
    - - Recombinant hGH (rhGH) is single isoform (22kDa)
      - Isoform test approach
        
        Increase in 22kDa isoform → a strong decrease in other native form
        
        isoform specific antibody to test the concentration ratio
        
        1-2 day window
      - Biomarkers test approach
        
        Increase in 22kDa isoform → increase the concentration of IGF-1 and type III pro-collagen #
        
        Testing the concentration of IGF-1 and Type III pro-collagen
        
        2-3 week window
  - - - D1 domain (distal to the membrane) - two disulfide linakge
        
        maintenance of structural and functional integrity
      - D2 domain (proximal to the membrane) - WSXWS motif
        
        critical for protein folding
        
        aromatic rings interact with the conserved Arg forming a Trp/Arg stacking which stabilizes D2
  - - - Homodimeric receptor complex but GH is asymmetric
      - different loops at the D1-D2 interface invloved
        
        R1: concave surface with high affinity
        
        R2: flat surface with low affinity
        
        Stem-stem interaction between two D2 enable cooperative binding of R2 (higher affinity than R2 alone)
    - - In vitro
        
        At low [GH], R1 and R2 binds to the same GH (increase in affinity) - active agonist
        
        At high [GH], R2 binds to a different GH, - inactive antagonist.
        
        expecting a bell-shape dose response curve
      - In vivo
        
        high [GH] is not available
        
        GHR exists as pre-formed dimer. (symmetric in resting state; asymmetric in GH-bound state)