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Predicting protein structure and function

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Not all proteins are enzymes: ... Burried and Edge strands. Parallel -sheet. Anti-parallel -sheet. Periodicity patterns. Burried -strand. Edge -strand -helix ... – PowerPoint PPT presentation

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Title: Predicting protein structure and function


1
Predicting protein structure and function
2
Protein function
Genome/DNA Transcriptome/mRNA Proteome Metabolo
me 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 -gt internal ?-strand
  • MA alternating (1-1) hydrophobic/hydrophilic gt
    edge ?-strand
  • MA alternating 2-2 (or 3-1) periodicity gt
    ?-helix
  • MA gaps in loops
  • MA Conserved column gt functional? gt 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 gt more
    residues to cross protein
  • ?-?-? motif is right-handed in gt95 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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