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The FREAKS Session 3 .1: Repeats Session 3 .2: Biased regions

The FREAKS Session 3 .1: Repeats Session 3 .2: Biased regions. of PROTEIN SEQUENCE. Miguel Andrade Johannes-Gutenberg University of Mainz A ndrade @uni-mainz.de. Frequency. 14% proteins contains repeats (Marcotte et al, 1999) 1: Single amino acid repeats.

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The FREAKS Session 3 .1: Repeats Session 3 .2: Biased regions

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  1. The FREAKS Session 3.1: Repeats Session 3.2: Biased regions of PROTEIN SEQUENCE Miguel Andrade Johannes-Gutenberg University of Mainz Andrade@uni-mainz.de

  2. Frequency 14% proteins contains repeats(Marcotte et al, 1999) 1: Single amino acid repeats. 2: Longer imperfect tandem repeats. Assemble in structure.

  3. Definition repeats Sequence, long, imperfect, tandem MRAVVKSPIMCHEKSPSVCSPLNMTSSVCSPAGINSVSSTTASF GSFPVHSPITQGTPLTCSPNVENRGSRSHSPAHASNVGSPLSSPLSSMKSSISSPPSHCSVKSPVSSPNNVTLRSSVSSPANINN

  4. Definition repeats Sequence, long, imperfect, tandem MRAVVKSPIMCHEKSPSVCSPLNMTSSVCSPAGINSVSSTTASFGSFPVHSPITQGTPLTCSPNVENRGSRSHSPAHASNVGSPLSSPLSSMKSSISSPPSHCSVKSPVSSPNNVTLRSSVSSPANINN

  5. Definition repeats Sequence, long, imperfect, tandem MRAVVKSPIM CHE KSPSVCSPLN MTSSVCSPAG INSVSSTTASF GSFPVHSPIT Q GTPLTCSPNV EN RGSRSHSPAH ASN VGSPLSSPLS S MKSSISSPPS HCS VKSPVSSPNN VT LRSSVSSPAN INN

  6. Definition repeats Sequence, long, imperfect, tandem MRAVVKSPIM CHE KSPSVCSPLN MTSSVCSPAG INSVSSTTASF GSFPVHSPIT Q GTPLTCSPNV EN RGSRSHSPAH ASN VGSPLSSPLS S MKSSISSPPS HCS VKSPVSSPNN VT LRSSVSSPAN INN

  7. Tandem repeats fold together

  8. Tandem repeats fold together

  9. Tandem repeats fold together

  10. Tandem repeats fold together

  11. Tandem repeats fold together

  12. Tandem repeats fold together

  13. Definition repeats Sequence, long, imperfect, tandem MRAVVKSPIM CHE KSPSVCSPLN MTSSVCSPAG INSVSSTTASF GSFPVHSPIT Q GTPLTCSPNV EN RGSRSHSPAH ASN VGSPLSSPLS S MKSSISSPPS HCS VKSPVSSPNN VT LRSSVSSPAN INN

  14. http://weblogo.berkeley.edu (Vlassi et al, 2013)

  15. Andrade et al. (2001) J Struct Biol

  16. Definition CBRs Perfectrepeat: QQQQQQQQQQQ Imperfect: QQQQPQQQQQQ Aminoacid type: DDDDDEEEDEDEED Compositionallybiasedregions (CBRs) High frequencyofoneortwoaminoacids in a region. Particularcaseoflowcomplexityregion

  17. Detection CBRs Sometimes straightforward. N-terminal human Huntingtin. How many CBRs can you find? >sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQP LLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPE FQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNGAP RSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFG NFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLV PVEDEHSTLLILGVLLTLRYLVPLLQQQVKDTSLKGSFGVTRKEMEVSPSAEQLVQVYEL TLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSI VELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAA SSGVSTPGSAGHDIITEQPRSQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAV PSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQD EDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQE NKPCRIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVG AAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSIL

  18. Detection CBRs Sometimes straightforward. N-terminal human Huntingtin. How many CBRs can you find? >sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQP LLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPE FQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNGAP RSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFG NFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLV PVEDEHSTLLILGVLLTLRYLVPLLQQQVKDTSLKGSFGVTRKEMEVSPSAEQLVQVYEL TLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSI VELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAA SSGVSTPGSAGHDIITEQPRSQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAV PSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQD EDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQE NKPCRIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVG AAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSIL

  19. Detection CBRs Sometimes straightforward. N-terminal human Huntingtin. How many CBRs can you find? >sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQP LLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPE FQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNGAP RSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFG NFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLV PVEDEHSTLLILGVLLTLRYLVPLLQQQVKDTSLKGSFGVTRKEMEVSPSAEQLVQVYEL TLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSI VELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAA SSGVSTPGSAGHDIITEQPRSQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAV PSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQDEDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQE NKPCRIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVG AAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSIL

  20. Detection CBRs Sometimes straightforward. N-terminal human Huntingtin. How many CBRs can you find? >sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQP LLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPE FQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNGAP RSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFG NFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLV PVEDEHSTLLILGVLLTLRYLVPLLQQQVKDTSLKGSFGVTRKEMEVSPSAEQLVQVYEL TLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSI VELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAA SSGVSTPGSAGHDIITEQPRSQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAV PSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQDEDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQE NKPCRIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVG AAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSIL

  21. Detection repeats Sometimes straightforward. N-terminal human Huntingtin. How many repeats can you find? >sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQP LLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPE FQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNGAP RSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFG NFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLV PVEDEHSTLLILGVLLTLRYLVPLLQQQVKDTSLKGSFGVTRKEMEVSPSAEQLVQVYEL TLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSI VELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAA SSGVSTPGSAGHDIITEQPRSQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAV PSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQD EDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQE NKPCRIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVG AAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSIL

  22. Detection repeats Often NOT straightforward. N-terminal human Huntingtin. How many repeats can you find? >sp|P42858|HD_HUMAN Huntingtin OS=Homo sapiens MATLEKLMKAFESLKSFQQQQQQQQQQQQQQQQQQQQQPPPPPPPPPPPQLPQPPPQAQP LLPQPQPPPPPPPPPPGPAVAEEPLHRPKKELSATKKDRVNHCLTICENIVAQSVRNSPEFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKALMDSNLPRLQLELYKEIKKNGAP RSLRAALWRFAELAHLVRPQKCRPYLVNLLPCLTRTSKRPEESVQETLAAAVPKIMASFG NFANDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHSRRTQYFYSWLLNVLLGLLV PVEDEHSTLLILGVLLTLRYLVPLLQQQVKDTSLKGSFGVTRKEMEVSPSAEQLVQVYELTLHHTQHQDHNVVTGALELLQQLFRTPPPELLQTLTAVGGIGQLTAAKEESGGRSRSGSI VELIAGGGSSCSPVLSRKQKGKVLLGEEEALEDDSESRSDVSSSALTASVKDEISGELAA SSGVSTPGSAGHDIITEQPRSQHTLQADSVDLASCDLTSSATDGDEEDILSHSSSQVSAV PSDPAMDLNDGTQASSPISDSSQTTTEGPDSAVTPSDSSEIVLDGTDNQYLGLQIGQPQD EDEEATGILPDEASEAFRNSSMALQQAHLLKNMSHCRQPSDSSVDKFVLRDEATEPGDQE NKPCRIKGDIGQSTDDDSAPLVHCVRLLSASFLLTGGKNVLVPDRDVRVSVKALALSCVG AAVALHPESFFSKLYKVPLDTTEYPEEQYVSDILNYIDHGDPQVRGATAILCGTLICSIL

  23. Detection repeats Often NOT straightforward. N-terminal human Huntingtin. How many repeats can you find? EFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKA CRPYLVNLLPCLTRTSKRP-EESVQETLAAAVPKIMASNDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHS TQYFYSWLLNVLLGLLVPVEDEHSTLLILGVLLTLRYL PSAEQLVQVYELTLHHTQHQDHNVVTGALELLQQLFRT

  24. Detection repeats Often NOT straightforward. N-terminal human Huntingtin. How many repeats can you find? EFQKLLGIAMELFLLCSDDAESDVRMVADECLNKVIKA CRPYLVNLLPCLTRTSKRP-EESVQETLAAAVPKIMASNDNEIKVLLKAFIANLKSSSPTIRRTAAGSAVSICQHS TQYFYSWLLNVLLGLLVPVEDEHSTLLILGVLLTLRYL PSAEQLVQVYELTLHHTQHQDHNVVTGALELLQQLFRT

  25. The FREAKS Session 3.1: Repeats Session 3.2: Biased regions of PROTEIN SEQUENCE Miguel Andrade Johannes-Gutenberg University of Mainz Andrade@uni-mainz.de

  26. Frequency repeats Fraction of proteins annotated with the keyword REPEAT in SwissProt % Archaea 27/3428 0.79 Viruses 81/8048 1.00 Bacteria 299/28438 1.05 Fungi 232/8334 2.78 Viridiplantae 153/6963 2.20 Metazoa 1538/28948 5.31 Rest of Eukaryota 92/2434 3.78 (Andrade et al 2001)

  27. Detection of repeats Dotplots Comparing a sequence against itself

  28. Detection of repeats Dotplots TLRSSVSSPANINNS NMTSSVCSPANISV

  29. Detection of repeats Dotplots TLRSSVSSPANINNS | 1 match NMTSSVCSPANISV

  30. Detection of repeats Dotplots TLRSSVSSPANINNS ||| ||||| 8 matches NMTSSVCSPANISV

  31. Detection of repeats Dotplots TLRSSVSSPANINNS | | 2 matches NMTSSVCSPANISV

  32. Detection of repeats Dotplots TLRSSVSSPANINNS | 1 match NMTSSVCSPANISV

  33. Detection of repeats Dotplots TLRSSVSSPANINNS NMTSSVCSPANISV 8

  34. Detection of repeats Dotplots TLRSSVSSPANINNS NMTSSVCSPANISV 1821

  35. Exercise 1

  36. Exercise 1. Using Dotlet with the human mineralocorticoid receptor (MR) • Obtain the sequence from UniProt • Go to the Dotlet web page • Click on the input button and paste the sequence there • Try to find combinations of parameters that show patterns in the dot plot • Find repetitions clicking in the diagonal patterns

  37. Detection of repeats Using a multiple sequence alignment helps Conserved repeated patterns JalView with Regular Expression searches

  38. Detection of repeats Using a multiple sequence alignment helps Conserved repeated patterns JalView with Regular Expression searches

  39. Detection of repeats Using a multiple sequence alignment helps Conserved repeated patterns JalView with Regular Expression searches

  40. Detection of repeats Using a multiple sequence alignment helps Conserved repeated patterns JalView with Regular Expression searches • Regular Expressions: [LS]P.A matches L or S, followed by P, followed by anything, followed by A

  41. Detection of repeats Using a multiple sequence alignment helps Conserved repeated patterns JalView with Regular Expression searches • Regular Expressions: [LS]P.A matches L or S, followed by P, followed by anything, followed by A Which one is not matched? • LPTA, SPAA, LPPA, LPAP, SPLA

  42. Detection of repeats Using a multiple sequence alignment helps Conserved repeated patterns JalView with Regular Expression searches • Regular Expressions: [LS]P.A matches L or S, followed by P, followed by anything, followed by A Which one is not matched? • LPTA, SPAA, LPPA, LPAP, SPLA

  43. Exercise 2. Using JalView with a MSA of the MR with orthologs • RunJalView using the JNLP file in desktop(from http://www.jalview.org/Download) • Load this MSA in JalView • Use the "find" option with a regular expression and mark all matches • Try to find the expression that matches more repeats. How many repeats do you see? How long are they? Would you correct the alignment based on these findings?

  44. #T7 #T1 #T2 #T3 #T4 #T5 #T6 * * * * #F4 #F3 #F2 #F1 #T14 #T8 #T9 #T10 #T11 #T12 #T13 #T15 * * * #F5 #F6 #F7 #F8 #F9 #F10 #F11 (Vlassi et al, 2013)

  45. Andrade and Bork (1995) Nature Genetics

  46. A subunit PP2A structure PDB:1b3u Groves et al. (1999) Cell

  47. Ap1 Clathrin Adaptor Core PDB:1w63 Heldwein et al. (2004) PNAS

  48. Ap1 Clathrin Adaptor Core PDB:1w63 Heldwein et al. (2004) PNAS

  49. Neural Network! Secondary structure Transmembrane helices Residue exposure Andrade, Petosa, O'Donoghue, Müller and Bork (2001) J Mol Biol

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