Transcript
Page 1: 3DSIG 2016 Presentation: Exploring Internal Symmetry and Structural Repeats with CE-Symm

EXPLORING INTERNAL SYMMETRY AND STRUCTURAL REPEATS WITH CE-SYMMSpencer BlivenJuly 8, 20163DSIG. Orlando, FL

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LEVELS OF SYMMETRY: QUATERNARY SYMMETRY DNA Clamps are found

as dimers in bacteria or trimers in eukaryotes

DNA is bound in the central channel

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

Stoichiometry: A3Symmetry: C3

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LEVELS OF SYMMETRY: SYMMETRY OF DOMAINS 6 “processivity fold”

domains

Proliferating Cell Nuclear Antigen [1VYM]

Stoichiometry: A6Symmetry: C6

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LEVELS OF SYMMETRY: INTERNAL SYMMETRY

Kelman, Z., & O'Donnell, M. (1995). Nucleic Acids Research, 23(18), 3613–3620.Neuwald, A. F., & Poleksic, A. (2000). Nucleic Acids Research, 28(18), 3570–3580.

Stoichiometry: A12Symmetry: D6

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SIGNIFICANCE Evolution

Identify duplications & fusions Many examples of homologous quaternary symmetric/internally

symmetric proteins Tradeoff between monomer & oligomer

Ancient protomer (x2?)

x6

Bacterial DimerEukaryotic/Archaeal/Viral Trimer

x2x3

DNA polymerase IIIβ

E. coli[1MMI]

Proliferating Cell Nuclear Antigen

Human[1VYM]

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SIGNIFICANCE

Function Allosteric regulation/cooperativity Bind ligands symmetrically (e.g. metals,

palindromic DNA, channels)

Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118.

TATA Binding Protein [1TGH]

Hemoglobin[4HHB]

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SIGNIFICANCE

Function Allosteric regulation/cooperativity Bind ligands symmetrically (e.g. metals,

palindromic DNA, channels) Folding

Prevent infinite assembly Subunits fold quasi-independently

TATA Binding Protein [1TGH]

Monod, J., Wyman, J., & Changeux, J.-P. (1965). J Mol Biol, 12, 88–118.Wolynes, P. G. (1996). PNAS, 93(25), 14249–14255.

Hemoglobin[4HHB]

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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

ɣB-Crystallin[4GCR]C2+C2

Vitamin C transporter

[4RP8]C2+C2/Broken D2

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CE-SYMM 2.0

Multiple alignment between all repeats Open and Closed symmetry Multiple Axes and hierarchical symmetry Point Group detection Monte Carlo alignment optimization https://github.com/rcsb/symmetry (LGPL)Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014).

Systematic Detection of Internal Symmetry in Proteins Using CE-Symm. Journal of Molecular Biology, 426(11), 2255–2268

Glyoxalase[3B59]

D2

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Monoamine Oxidase Regulatory Protein [1Q6W]

DIFFERENT STOICHIOMETRY, SAME STRUCTURE

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Monoamine Oxidase Regulatory Protein [1Q6W]

DIFFERENT STOICHIOMETRY, SAME STRUCTURE

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Monoamine Oxidase Regulatory Protein [1Q6W]

MaoC domain protein dehydratase [4E3E]

DIFFERENT STOICHIOMETRY, SAME STRUCTURE

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Monoamine Oxidase Regulatory Protein [1Q6W]

MaoC domain protein dehydratase [4E3E]

DIFFERENT STOICHIOMETRY, SAME STRUCTURE

A6 stoichiometryD3 symmetry

A3 stoichiometryC3 symmetry?

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Monoamine Oxidase Regulatory Protein [1Q6W]

MaoC domain protein dehydratase [4E3E]

DIFFERENT STOICHIOMETRY, SAME STRUCTURE

[ND]xxxxH

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PROMINENT IN MEMBRANE PROTEINS Major Facilitator

Superfamily Lactose/Proton symporter Lactose binds at center 4 repeats (2 inverted)

periplasm

cytosol

LacY[1Q6W]

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CE-SYMM 2.0 ALGORITHMStructure

1. Structural Self Alignment

Self-Alignment

TM-Score

2.Order Detection

Order

3. Refinement

Multiple Alignment

4. Optimization

TM-ScoreAsymmetry Symmetry

6. Point Group Detection

5. Iterate

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CE-SYMM 2.0 ALGORITHMStructure

1. Structural Self Alignment

Self-Alignment

TM-Score

2.Order Detection

Order

3. Refinement

Multiple Alignment

4. Optimization

TM-ScoreAsymmetry Symmetry

6. Point Group Detection

5. IterateKeap1 Kelch

domain[1U6D]

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CE-SYMM 2.0 ALGORITHMStructure

1. Structural Self Alignment

Self-Alignment

TM-Score

Order

Multiple Alignment

4. Optimization

TM-ScoreAsymmetry Symmetry

6. Point Group Detection

5. Iterate

3. Refinement

Keap1 Kelch domain[1U6D]

2.Order Detection

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CE-SYMM 2.0 ALGORITHMStructure

1. Structural Self Alignment

Self-Alignment

TM-Score

2.Order Detection

Order

3. Refinement

Multiple Alignment

TM-ScoreAsymmetry Symmetry

6. Point Group Detection

5. Iterate

4. Optimization

Keap1 Kelch domain[1U6D]

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CE-SYMM 2.0 ALGORITHMStructure

1. Structural Self Alignment

Self-Alignment

TM-Score

2.Order Detection

Order

3. Refinement

Multiple Alignment

4. Optimization

TM-ScoreAsymmetry Symmetry

6. Point Group Detection

5. Iterate

Keap1 Kelch domain[1U6D]

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CENSUS All domains from SCOPe 2.06 Underestimate based on conservative thresholds

Order Number of Superfamilies

% symmetric

Asymmetric 1051 75.39%Rotational 302 21.66%

C2 237 78.48%C3 19 6.29%C4 12 3.97%C5 2 0.66%C6 8 2.65%C7 16 5.30%C8 8 2.65%

Dihedral 19 1.36%D2 17 89.47%D3 2 10.53%

Helical 7 0.50%Translationa

l 15 1.08%

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SUMMARY

Nature utilizes symmetry at multiple levels

Internal symmetry can reveal evolutionary history of folds

Duplications & fusions can preserve the overall biological assembly

Internal symmetry is a multiple alignment problem

CE-Symm is able to automatically detect most types of structural repeats

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ACKNOWLEDGEMENTS Paul Scherrer Institute

Guido Capitani Aleix Lafita

UC San Diego/RCSB Douglas Myers-Turnbull Andreas Prlić Peter Rose Jose Duarte RCSB & Bourne Lab

members NIH

Philip Bourne Philippe Youkharibache David Landsman

Resources: github.com/rcsb/symmetry source.rcsb.org/

jfatcatserver/symmetry.jsp www.slideshare.net/sbliven

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

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RNA INTERNAL SYMMETRY

FMN Riboswitch [3F4E]

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PTSIIA/GUTA-LIKE DOMAIN PTS sorbitol transporter subunit IIA Novel fold Solved by the Protein Structure Initiative Structural alignment reveals a conserved sequence motif

between halves

2F9H

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ABC TRANSPORTER

BtuF

BtuC

BtuD

Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

Periplasmic-binding protein

Transmembrane domain

Nucleotide-binding domain

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ABC TRANSPORTER

BtuF [1N4A]

BtuF

BtuC

BtuD

Vitamin B12 transporter BtuCD–F from E. coli [4FI3]

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BENCHMARK 1007 structures from SCOP

superfamilies Manually curated Excludes small proteins (<4

SSEs) 26% of superfamilies have

internal symmetry or large structural repeats

Order Superfamilies

%

Asymmetric

747 74.2%

Rotational 214 21.2%2 160 74.8%3 10 4.7%4 2 0.9%5 3 1.4%6 9 4.2%7 10 4.7%8 20 9.3%

Dihedral 18 1.8%D2 14 77.8%D3 1 5.6%D4 2 11.1%D5 1 5.6

Helical 11 1.1%H2 9 81.8%H3 2 18.2%

H10 1 9.1%Superhelical

2 0.2%

Translational

15 1.5%

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PERFORMANCE

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PERFORMANCE

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CE-SYMM: SELF-ALIGNMENT

Fibroblast Growth Factor

[3JUT]

120° 120°

Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268.

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CE-SYMM: SELF-ALIGNMENT

Fibroblast Growth Factor

[3JUT]

120° 120°

Myers-Turnbull, D., Bliven, S. E., Rose, P. W., Aziz, Z. K., Youkharibache, P., Bourne, P. E., & Prlić, A. (2014). Journal of Molecular Biology, 426(11), 2255–2268.

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βγ-CRYSTALLIN FAMILY

Aravind, P., Mishra, A., Suman, S. K., Jobby, M. K., Sankaranarayanan, R., & Sharma, Y. (2009). The betagamma-crystallin superfamily contains a universal motif for binding calcium. Biochemistry, 48(51), 12180–12190.

M-Crystallin[3HZ2.A]

C2

Bovine ɣB-Crystallin[4GCR]C2+C2

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