Repetitive Beta Folds

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
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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

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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

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Trimeric Viral Attachment Fiber Proteins
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Trimeric Viral Attachment Fibers

• Kings 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

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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

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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

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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-qu
  eries.pl
• TBH has so far defied basic characterization
• Only two solved structures
• The quasi-repeat is less regular than the TBS

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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

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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_at_mit.edu)
• and
• Eben Scanlon (eben_at_mit.edu)

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Supplemental Slides
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TBS Information

• Human Adenovirus 2 Fiber and Reovirus Attachment
  Protein s1 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 IDs are 1kke, 1qiu

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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 IDs are 1H6W, 1K28
• Need to use PQS (http//pqs.ebi.ac.uk) to get
  trimer image