Predicting%20The%20Beta-Helix%20Fold%20From%20Protein%20Sequence%20Data

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Predicting The Beta-Helix Fold From Protein
Sequence Data Phil Bradley, Lenore Cowen,
Matthew Menke, Jonathan King, Bonnie Berger
MIT
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Structural Motif Recognition
Problem Given a structural motif (secondary,
super-secondary, tertiary), predict its presence
from sequence data alone.
Example Coiled-coil prediction (Berger et al.
1995)
GCN4 leucine zipper
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Long Distance Correlations
In beta structures, amino acids close in the
folded 3D structure may be far away in the linear
sequence
Cyclophilin A
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The Right-handed Parallel Beta-Helix
A processive fold composed of repeated
super-secondary units. Each rung consists of
three beta-strands separated by turn regions. No
sequence repeat.
Pectate Lyase C (Yoder et al. 1993)
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Biological Importance of Beta Helices

• Surface proteins in human infectious disease
• virulence factors
• adhesins
• toxins
• allergens
• Proposed as a model for amyloid fibrils (e.g.
  Alzheimers and CJD)
• Virulence factors in plant pathogens

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What is Known
Solved beta-helix structures 12 structures in
PDB in 7 different SCOP families
Pectate Lyase Pectate Lyase C Pectate
Lyase E Pectate Lyase Galacturonase
Polygalacturonase Polygalacturonase II
Rhamnogalacturonase A
Pectin Lyase Pectin Lyase A Pectin Lyase
B Chondroitinase B Pectin Methylesterase P.69
Pertactin P22 Tailspike
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Approaches to Structural Motif Recognition
General Methods Sequence similarity
searches Multiple alignments profile
HMMs Threading Profile methods (3D 1D)
-Heffron et al. (1998) Statistical Methods
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BetaWrap Program

• Performance
• On PDB no false positives no false negatives.
  Recognizes beta helices in PDB across SCOP
  families in cross-validation.
• Recognizes many new potential beta helices when
  run on larger sequence databases.
• Runs in linear time (5 min. on SWISS-PROT).

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BetaWrap Program

• Histogram of protein scores for
• beta helices not in database (12 proteins)
• non-beta helices in PDB (1346 proteins )

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Single Rung of a Beta Helix
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3D Pairwise Correlations

Aligned residues in adjacent beta-strands
exhibit strong correlations Residues in the T2
turn have special correlations (Asparagine
ladder, aliphatic stacking)
B1
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3D Pairwise Correlations


Stacking residues in adjacent beta-strands
exhibit strong correlations Residues in the T2
turn have special correlations (Asparagine
ladder, aliphatic stacking)
B1
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Question how can we find these correlations
which are a variable distance apart in sequence?
Phage P22 Tailspike
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Finding Candidate Wraps

• Assume we have the correct locations of a
• single T2 turn (fixed B2 B3).

Candidate Rung
B3
T2
B2

• Generate the 5 best-scoring candidates for the
  next rung.

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Scoring Candidate Wraps (rung-to-rung)
Rung-to-rung alignment score incorporates

• Beta sheet pairwise alignment preferences taken
  from amphipathic beta structures in PDB.
• (w/o beta helices)
• Additional stacking bonuses
• on internal pairs.
• Distribution on turn lengths.

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Scoring Candidate Wraps (5 rungs)

• Iterate out to 5 rungs generating candidate
  wraps

• Score each wrap
• - sum the rung-to-rung scores
• - B1 correlations filter
• - screen for alpha-helical content

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Key Features of Our Approach

• Structural model
• Statistical score
• Dynamic search

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Predicted Beta Helices

• Features of the 200 top-scoring proteins in the
  NCBIs protein sequence database
• Many proteins of similar function to the known
  beta-helices some with similar sequences.
• A significant fraction are characterized as
  microbial outer membrane or cell-surface
  proteins.
• Mouse, human, worm and fly sequences
  significantly underrepresented only two
  proteins!

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Some Predicted Beta Helices in Human Pathogens
Cholera Ulcers Malaria Venereal
infection Respiratory infection Listeriosis Sleepi
ng sickness Lyme disease Leishmaniasis Respiratory
infection Sleeping sickness Whooping
cough Anthrax Rocky Mtn. spotted fever Oriental
spotted fever Meningitis Legionnaires disease
Vibrio cholerae Helicobacter pylori Plasmodium
falciparum Chlamyidia trachomatis
Chlamydophilia pneumoniae Listeria
monocytogenes Trypanosoma brucei Borrelia
burgdorferi Leishmania donovani Bordetella
bronchiseptica Trypanosoma cruizi Bordetella
parapertussis Bacillus anthracis Rickettsia
ricketsii Rickettsia japonica Neisseria
meningitidis Legionaella pneumophilia
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Predicted Beta Helices
False positives? Also present in the top 200
proteins are members of the LRR and hexapeptide
repeat families.
Hexapeptide repeat
LRR
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Structural Features of Beta-Helices

• B2-T2-B3 region is well-conserved.
• T1 and T3 turns highly variable (from 2 to 63
  residues in length).
• Active site is an extended surface, formed by T3,
  B1, T1.
• Distinctive internal stacking interactions.

A single rung of Pectate Lyase C