Lecture 3-2008

Lecture 3-2008 - Evolutionary (or Structural) Relationships...

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Evolutionary (or Structural) Relationships Structure follows function. Similarity between structures implies a relationship: functional and evolutionary. How can we tell if two proteins are related?
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Homologs : Proteins which are related in their primary sequence Similar sequences translate into similar 3D structures 3D structure more highly conserved than primary sequence Two Homologs
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3D Structure is more highly conserved Another homolog Angiogenin is 35% identical in sequence to ribonuclease. Angiogenin has a different function: Stimulate growth of new blood vessels Its 3D structure is more closely related than expected from the sequence identity level
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Two Classes of Homologs Homologs are descendants of a common evolutionary ancestor. Paralogs: Homologs present in one species. Often differ in biochemical function. Orthologs : Present in different species. Have the same or related function
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3D structures are hard to come by. Homology is often seen in nucleotide or amino acid sequences. Genomes (human, mouse, yeast, Drosophila , C. elegans, etc. ) can be translated into protein in silico , so we have the primary amino acid sequence of all possible proteins in databases. Amino acid sequence comparisons usually more effective because 20 amino acids vs. 4 nucleotides.
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Sequence Analysis Members of the globin family Make sequence alignment Insertions/Deletions Compare amino acid sequences, not DNA sequences Significant similarity implies evolutionary relationship and related 3D structures.
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38 identical residues! Gap penalties Alignment score: 10 points for each identical residues -25 points for each gap (more sophisticated approach: also gap extension penalties) Significance of alignment: Sequence shuffling Gapped Sequence Alignment
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Hemoglobin/myoglobin Shuffled sequences
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Conservative substitutions allows more accurate comparisons
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BLOSUM-62 Substitution Matrix Better scoring system. Test your knowledge of the amino acid structures and properties.
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Distant Sequence Relationships Use BLOSUM-62 or similar substitution matrix Myoglobin and leghemoglobin are 23% identical • Leghemoglobin:O 2 -binding protein from plant roots > 25% identity: almost certainly not a chance event < 15% identity: no statistically significant relationships can be detected 15 - 25%:Gray zone, further investigations are needed Distinguish between conservative (yellow) and non-conservative substitutions
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Myoglobin-leghemoglobin: 23% identity Hemoglobin-leghemoglobin: 15.6% identity Sequence alignments can be improved if the 3D structures are known Conserved over a long evolutionary period (much time to change) 3D Structure Conservation
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Convergent Evolution Convergent Evolution: Unrelated 3D structures, not derived from common ancestor.
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Lecture 3-2008 - Evolutionary (or Structural) Relationships...

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