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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.
GCN4 leucine zipper
Example: Coiled-coil prediction (Berger et al. 1995)
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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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A processive fold composed of repeated super-secondary units.
Each rung consists of three beta-strands separated by turn regions.
No sequence repeat.
The Right-handed Parallel Beta-Helix
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. Alzheimer’s 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 BPectin MethylesteraseP.69 PertactinP22 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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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).
BetaWrap Program
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BetaWrap ProgramHistogram 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)
B3T2
B2
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)
B3T2
B2
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).
• Generate the 5 best-scoring candidates for the next rung.
B2
B3 T2Candidate
Rung
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Scoring Candidate Wraps (rung-to-rung)
Rung-to-rung alignment score incorporates:
• Beta sheet pairwise alignmentpreferences taken from amphipathic beta structures in PDB.
(w/o beta helices)
• Additional stacking bonuseson 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 NCBI’s 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
Vibrio cholerae Helicobacter pyloriPlasmodium falciparum Chlamyidia trachomatis Chlamydophilia pneumoniae Listeria monocytogenes Trypanosoma brucei Borrelia burgdorferiLeishmania donovani Bordetella bronchiseptica Trypanosoma cruizi Bordetella parapertussisBacillus anthracisRickettsia ricketsii Rickettsia japonicaNeisseria meningitidisLegionaella pneumophilia
CholeraUlcersMalariaVenereal infectionRespiratory infectionListeriosisSleeping sicknessLyme diseaseLeishmaniasisRespiratory infectionSleeping sicknessWhooping coughAnthraxRocky Mtn. spotted feverOriental spotted feverMeningitisLegionnaire’s disease
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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 repeatLRR
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•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.
Structural Features of Beta-Helices
A single rung of Pectate Lyase C