3DSIG 2016 Presentation: Exploring Internal Symmetry and Structural Repeats with CE-Symm

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Following the Evolution of New Protein Folds Via Protodomains

Exploring Internal Symmetry and Structural Repeats with CE-SymmSpencer BlivenJuly 8, 20163DSIG. Orlando, FL

Levels of Symmetry: Quaternary SymmetryDNA Clamps are found as dimers in bacteria or trimers in eukaryotesDNA is bound in the central channel

Proliferating Cell Nuclear Antigen [1VYM](DNA modeled from 1BNA)

Stoichiometry: A3Symmetry: C31

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Levels of Symmetry: Symmetry of Domains6 processivity fold domains

Proliferating Cell Nuclear Antigen [1VYM]Stoichiometry: A6Symmetry: C6

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Levels of Symmetry: Internal SymmetryKelman, Z., & O'Donnell, M. (1995). Nucleic Acids Research, 23(18), 36133620.Neuwald, A. F., & Poleksic, A. (2000). Nucleic Acids Research, 28(18), 35703580.Stoichiometry: A12Symmetry: D6

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SignificanceEvolutionIdentify duplications & fusionsMany examples of homologous quaternary symmetric/internally symmetric proteinsTradeoff between monomer & oligomer4Ancient protomer (x2?)x6

Bacterial DimerEukaryotic/Archaeal/Viral Trimerx2x3

DNA polymerase IIIE. coli[1MMI]

Proliferating Cell Nuclear AntigenHuman[1VYM]

63% of symmetric domains have the ligand within 5 of the axis of symmetry, 37% within 1

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SignificanceFunctionAllosteric regulation/cooperativityBind ligands symmetrically (e.g. metals, palindromic DNA, channels)Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88118.TATA Binding Protein [1TGH]

Hemoglobin[4HHB]

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63% of symmetric domains have the ligand within 5 of the axis of symmetry, 37% within 1

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SignificanceFunctionAllosteric regulation/cooperativityBind ligands symmetrically (e.g. metals, palindromic DNA, channels)FoldingPrevent infinite assemblySubunits fold quasi-independentlyTATA Binding Protein [1TGH]

Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88118.Wolynes, P. G. (1996). PNAS, 93(25), 1424914255.

Hemoglobin[4HHB]

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63% of symmetric domains have the ligand within 5 of the axis of symmetry, 37% within 1

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Types of Symmetry

Cyclic (C8)TIM barrel[1TIM]Dihedral (D2)Glyoxalase[3B59]Helical (H3)Antifreeze Protein[1L0S]Translational (R)Ankyrin Repeat[1N0R]

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Hierarchical Symmetry

B-Crystallin[4GCR]C2+C2Vitamin C transporter[4RP8]C2+C2/Broken D2

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CE-Symm 2.0Multiple alignment between all repeatsOpen and Closed symmetryMultiple Axes and hierarchical symmetryPoint Group detectionMonte Carlo alignment optimizationhttps://github.com/rcsb/symmetry (LGPL)

Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prli, A. (2014). Systematic Detection of Internal Symmetry in Proteins Using CE-Symm. Journal of Molecular Biology, 426(11), 22552268

Glyoxalase[3B59]D2

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Monoamine Oxidase Regulatory Protein [1Q6W]Different Stoichiometry, Same Structure10

Fatty acid synthesis proteins

TODO add double hotdog, read up more on functions

Photo public domain http://www.publicdomainpictures.net/view-image.php?image=121204&picture=hotdog-mustard-onlyTop image actually 1q6w for simplicity10

Monoamine Oxidase Regulatory Protein [1Q6W]

Different Stoichiometry, Same Structure11

Fatty acid synthesis proteins

TODO add double hotdog, read up more on functions

Photo public domain http://www.publicdomainpictures.net/view-image.php?image=121204&picture=hotdog-mustard-onlyTop image actually 1q6w for simplicity11

Monoamine Oxidase Regulatory Protein [1Q6W]MaoC domain protein dehydratase [4E3E]Different Stoichiometry, Same Structure12

Fatty acid synthesis proteins

Photo public domain http://www.publicdomainpictures.net/view-image.php?image=121204&picture=hotdog-mustard-onlyhttps://pixabay.com/en/hot-dogs-frankfurters-bun-meat-1047824/12

Monoamine Oxidase Regulatory Protein [1Q6W]MaoC domain protein dehydratase [4E3E]Different Stoichiometry, Same Structure13

A6 stoichiometryD3 symmetryA3 stoichiometryC3 symmetry?

Fatty acid synthesis proteins

TODO add double hotdog, read up more on functions

Photo public domain http://www.publicdomainpictures.net/view-image.php?image=121204&picture=hotdog-mustard-onlyTop image actually 1q6w for simplicity13

Monoamine Oxidase Regulatory Protein [1Q6W]MaoC domain protein dehydratase [4E3E]Different Stoichiometry, Same Structure

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[ND]xxxxH

Fatty acid synthesis proteins

TODO add double hotdog, read up more on functions

Photo public domain http://www.publicdomainpictures.net/view-image.php?image=121204&picture=hotdog-mustard-onlyTop image actually 1q6w for simplicity14

Prominent in Membrane ProteinsMajor Facilitator SuperfamilyLactose/Proton symporterLactose binds at center4 repeats (2 inverted)

periplasmcytosol15

LacY[1Q6W]

CE-Symm 2.0 AlgorithmStructure1. Structural Self AlignmentSelf-AlignmentTM-Score2.Order DetectionOrder3. RefinementMultiple Alignment4. OptimizationTM-ScoreAsymmetrySymmetry6. Point Group Detection5. Iterate16

CE-Symm 2.0 AlgorithmStructure1. Structural Self AlignmentSelf-AlignmentTM-Score2.Order DetectionOrder3. RefinementMultiple Alignment4. OptimizationTM-ScoreAsymmetrySymmetry6. Point Group Detection5. Iterate

Keap1 Kelch domain[1U6D]17

CE-Symm 2.0 AlgorithmStructure1. Structural Self AlignmentSelf-AlignmentTM-ScoreOrderMultiple Alignment4. OptimizationTM-ScoreAsymmetrySymmetry6. Point Group Detection5. Iterate

3. RefinementKeap1 Kelch domain[1U6D]182.Order Detection

CE-Symm 2.0 AlgorithmStructure1. Structural Self AlignmentSelf-AlignmentTM-Score2.Order DetectionOrder3. RefinementMultiple AlignmentTM-ScoreAsymmetrySymmetry6. Point Group Detection5. Iterate

4. OptimizationKeap1 Kelch domain[1U6D]19

CE-Symm 2.0 AlgorithmStructure1. Structural Self AlignmentSelf-AlignmentTM-Score2.Order DetectionOrder3. RefinementMultiple Alignment4. OptimizationTM-ScoreAsymmetrySymmetry6. Point Group Detection5. Iterate

Keap1 Kelch domain[1U6D]20

CensusAll domains from SCOPe 2.06Underestimate based on conservative thresholds

21OrderNumber of Superfamilies% symmetricAsymmetric105175.39%Rotational30221.66%C223778.48%C3196.29%C4123.97%C520.66%C682.65%C7165.30%C882.65%Dihedral191.36%D21789.47%D3210.53%Helical70.50%Translational151.08%

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Summary

Nature utilizes symmetry at multiple levelsInternal symmetry can reveal evolutionary history of foldsDuplications & fusions can preserve the overall biological assemblyInternal symmetry is a multiple alignment problemCE-Symm is able to automatically detect most types of structural repeats

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AcknowledgementsPaul Scherrer InstituteGuido CapitaniAleix LafitaUC San Diego/RCSBDouglas Myers-TurnbullAndreas PrliPeter RoseJose DuarteRCSB & Bourne Lab membersNIHPhilip BournePhilippe YoukharibacheDavid LandsmanResources:github.com/rcsb/symmetrysource.rcsb.org/jfatcatserver/symmetry.jspwww.slideshare.net/sbliven

Funding: NCBI/NLM/NIHRCSB: NSF, NIH, DOE

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RNA Internal Symmetry

FMN Riboswitch [3F4E]25

PTSIIA/GutA-like domainPTS sorbitol transporter subunit IIANovel foldSolved by the Protein Structure InitiativeStructural alignment reveals a conserved sequence motif between halves2F9H

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Deposited 200526

ABC Transporter

BtuFBtuCBtuDVitamin B12 transporter BtuCDF from E. coli [4FI3]Periplasmic-binding proteinTransmembrane domainNucleotide-binding domain27

ABC Transporter

BtuF [1N4A]BtuFBtuCBtuDVitamin B12 transporter BtuCDF from E. coli [4FI3]28

Benchmark1007 structures from SCOP superfamiliesManually curatedExcludes small proteins (