Protein function (and structure)

Protein function (and structure)

1. DNA binding protein domains

   • many and varied
   • overall basic charge to mediate the interaction with the acidic DNA strand
     • mostly through interactions with the major groove
   • Several classes of DNA binding proteins containing:
     • zinc fingers
     • leucine zipper motifs
       • dimers of short coiled-coil sequence (the leucine zipper)
         • As dimers, often form homo- or hetero-dimers increasing the repertoire of available DNA binding proteins.
       • and a specific DNA recognition helix
       • Bind DNA like a ‘clothes peg’ on a washing line
     • basic helix-loop-helix (bHLH)
     • β-sheet
     • Some proteins have several motifs in tandem for increased affinity

2. Modular proteins

   • Made up of several different functional domains

3. Functional domains

4. SH2

   • Src Homology 2 domain
   • important phospho-tyrosine binding domain
     • Binds phosphorylated tyrosine
       • Often involved in signalling mechanisms
         • Binding of SH2 domains to their phospho-tyrosine ligands are involved in the formation of signalling complexes
       • Specific for phospho-tyrosine, but one SH2 domain may interact with p-Tyr in different contexts
         • Specificity is between the phosphate of the p-Tyr
           • some hydrogen bonding also contributes
           • mainly ionic interactions between -ve phosphate group and +ve aa’s,
   • Prototypical SH2 domain is from the protein tyrosine kinase Src
     • Also found in many other signalling and adaptor proteins

5. SH3

   • Involved in linking structural components
   • Structural roles in maintaining multi-protein complexes
   • Src Homology 3 domain
   • poly-proline binding domain acting as an adaptor to link proteins
     • Binds proline rich motifs
       • The minimum consensus sequence for SH3 binding is P-x-x-P,
         • SH3 domain contains several aromatic residues, these interdigitate between the prolines of the PxxP motif which is stabilised by aromatic stacking
   • Prototypical SH3 domain is from the protein tyrosine kinase Src, but also found in many other signalling and adaptor proteins

6. PH Domain

   • Binds phospholipids
     • Phospholipases
       • Phospholipases have a direct role in lipid signalling
     • interact with ionic head groups of phospho-lipids anchoring the protein to membrane
   • Role in lipid signalling
     • and lipid binding
     • And anchoring proteins to membranes
   • Spectrin
     • Structural role in maintaining membrane integrity
   • PH Pleckstrin Homology domain

7. EF Hand

   • octadentate, coordinating through 7 oxygen containing side chains
   • Invariant glycine residue to accommodate the tight turn
   • Binding
     • Ca2+/Mg2+ has a structural function
     • binding Ca2+ has a regulatory function
     • Calcium binding to EF-hands induces structural change e.g. calcium binding to calmodulin
   • back to ppt for diagram

8. Zinc finger

   • Binds zinc in a structural mode
   • usually structural function in protein-DNA or protein-protein interactions
   • Zn is coordinated tetrahedrally
     • usually by cysteine or histidine residues

9. Protein-Protein interactions

   • Require complementary surfaces
   • Bonds may be a combination of
     • Ionic
     • Hydrophobic
     • Electrostatic

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