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Repetitive Beta Folds

Repetitive Beta Folds. Form, Function, and Properties. Overview of Presentation. Introduction to traditional beta-helix fold Structural and functional properties Structure prediction by BetaWrap program Introduction to trimeric viral attachment fibers

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Repetitive Beta Folds

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  1. Repetitive Beta Folds Form, Function, and Properties

  2. Overview of Presentation • Introduction to traditional beta-helix fold • Structural and functional properties • Structure prediction by BetaWrap program • Introduction to trimeric viral attachment fibers • Structural comparison to traditional beta-helices • Current computational approaches

  3. Basic Parallel Beta-Helix Function: Sugar cleavage Beta-helix is an all beta fold Mainly occurs in bacterial pathogens Three strands per rung King lab studies RHBH Tailspike Right-handed helix (RHBH) Also left-handed helices (LHBH) Three faces form a prism

  4. Analyzing Beta-Helices • Solved structures • RHBH: 5 SCOP SuperFamilies • LHBH: 2 SCOP SuperFamilies • 48 solved structures in PDB • 8 HSSP representatives • Predicting novel beta-helices • Homology modeling, threading, and HMMs do not successfully predict occurrence in cross-validation • BetaWrap (King, Berger et al. 2001) successfully predicts RHBH

  5. Lessons from BetaWrap • Joint sequence-structure analysis important • Discovered conserved hairpin turn • Discovered internally packed asparagines • Beta-strand packing interactions are important • BetaWrap energy function uses strand-to-strand packing probabilities • Prediction is not enough • BetaWrap does not predict active site, etc. • Other methods (rotamer libraries etc.) may supplement initial prediction

  6. Trimeric Viral Attachment Fiber Proteins

  7. Trimeric Viral Attachment Fibers • King’s interest in beta helix led to interest in two new folds • Triple beta-helix (TBH) • Triple beta-spiral (TBS) • These two folds are our current research area • Consist of three identical interacting chains • TBH is structurally similar to beta-helix • TBS is structurally distinct • Both folds characterized by unusual stability to heat, protease, and detergent

  8. Triple Beta-Helix • Described by van Raaij et al. in JMB (2001) • HomoTrimeric (consists of three identical chains) • Two solved structures • Portion of T4 short tail fibre SwissProt: P10390 • Cell puncturing device of T4 SwissProt: P16009

  9. Triple Beta-Spiral • Described by van Raaij et al. in Nature (1999) • HomoTrimeric (three identical chains) • Two solved structures • Human Adenovirus 2 Fibre SwissProt: P03275 • Reovirus Attachment Fibre SwissProt: P03528 • Characterized by regular repeat pattern in literature

  10. Preliminary Analysis • TBS more regular than TBH • TBS characterized by sequence repeat • Can use standard regex techniques (like PROSITE) to find many putative TBSs • See http://www.baobob.net/cgi-bin/repeat/stored-queries.pl • TBH has so far defied basic characterization • Only two solved structures • The quasi-repeat is less regular than the TBS

  11. Current Research • What are we trying to do with TBH and TBS? • There are too few for rigorous prediction tool • Right now we are just “characterizing” them • Searching for sequence-structure patterns • Searching for unique properties • Searching for repetitive sequence motifs • Regular Expression is first attempt • Search with PSSM sequence profile

  12. Repetitive Sequence Motif Search • Existing Methods for repetitive motif search • RADAR (Heger & Holm) and others attempt this • Existing methods do not find the adeno repeat • TBH repeat is not regular enough to search • Our approaches (tried so far…) • Basic regular expression (more in supplemental) • PSSM characterizing repeat (in progress)

  13. Thank you Peter Weigele (pweigele@mit.edu) and Eben Scanlon (eben@mit.edu)

  14. Supplemental Slides

  15. TBS Information • Human Adenovirus 2 Fiber and Reovirus Attachment Protein σ1 have 27% sequence identity, 52% sequence similarity • Searching SwissProt for the Adenovirus repeat (regex) pattern with more than 6 occurrences finds 3158 matches • Searching SwissProt for the Reovirus repeat (regex) pattern finds 37578 matches • PDB ID’s are 1kke, 1qiu

  16. TBH Information • The T4 Short tail fiber TBH and the T4 cell puncturing TBH have 32% sequence identity and 61% sequence similarity • There is no clear repeat pattern in TBH • Tried PSSM and HMM models with alignments derived from known repeat strands in TBH • Have not yet figured out a way to restrict to matches with a large number of recurrent repeats • Also may want to add a high non-affine gap penalty beyond a certain extension • PDB ID’s are 1H6W, 1K28 • Need to use PQS (http://pqs.ebi.ac.uk) to get trimer image

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