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Predicting protein structure and function

Predicting protein structure and function. Protein function. Genome/DNA Transcriptome/mRNA Proteome Metabolome Physiome. Transcription factors. Ribosomal proteins Chaperonins. Enzymes. Protein function. Not all proteins are enzymes:

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Predicting protein structure and function

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  1. Predicting protein structure and function

  2. Protein function Genome/DNA Transcriptome/mRNA Proteome Metabolome Physiome Transcription factors Ribosomal proteins Chaperonins Enzymes

  3. Protein function Not all proteins are enzymes: -crystallin: eye lens protein – needs to stay stable and transparent for a lifetime (very little turnover in the eye lens)

  4. What can happen to protein function through evolution Proteins can have multiple functions (and sometimes many -- Ig). Enzyme function is defined by specificity and activity Through evolution: • Function and specificity can stay the same • Function stays same but specificity changes • Change to some similar function (e.g. somewhere else in metabolic system) • Change to completely new function

  5. How to arrive at a given function • Divergent evolution – homologous proteins –proteins have same structure and “same-ish” function • Convergent evolution – analogous proteins – different structure but same function • Question: can homologous proteins change structure (and function)?

  6. How to evolve Important distinction: • Orthologues: homologous proteins in different species (all deriving from same ancestor) • Paralogues: homologous proteins in same species (internal gene duplication) • In practice: to recognise orthology, bi-directional best hit is used in conjunction with database search program

  7. How to evolve By addition of domains (at either end of protein sequence) – Lesk book page 108 Often through gene duplication followed by divergence

  8. Structural domain organisation can be nasty… Pyruvate kinase Phosphotransferase b barrel regulatory domain a/b barrel catalytic substrate binding domain a/b nucleotide binding domain 1 continuous + 2 discontinuous domains

  9. The DEATH Domain • Present in a variety of Eukaryotic proteins involved with cell death. • Six helices enclose a tightly packed hydrophobic core. • Some DEATH domains form homotypic and heterotypic dimers. http://www.mshri.on.ca/pawson

  10. How to predict function • Sequence information: Homology searching • Sequence-structure information: Fold recognition (Threading) • Structure-structure information: structure superpositioning

  11. Flavodoxin fold 5() fold

  12. Rules of thumb when looking at a multiple alignment (MA) • Hydrophobic residues are internal • Gly (Thr, Ser) in loops • MA: hydrophobic block -> internal -strand • MA: alternating (1-1) hydrophobic/hydrophilic => edge -strand • MA: alternating 2-2 (or 3-1) periodicity => -helix • MA: gaps in loops • MA: Conserved column => functional? => active site

  13. Rules of thumb when looking at a multiple alignment (MA) • Active site residues are together in 3D structure • Helices often cover up core of strands • Helices less extended than strands => more residues to cross protein • -- motif is right-handed in >95% of cases (with parallel strands) • MA: ‘inconsistent’ alignment columns and match errors! • Secondary structures have local anomalies, e.g. -bulges

  14. Burried and Edge strands Parallel -sheet Anti-parallel -sheet

  15. Periodicity patterns Burried -strand Edge -strand -helix

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