PART II. Prediction of functional regions within disordered proteins Zsuzsanna Dosztányi MTA-ELTE...
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Transcript of PART II. Prediction of functional regions within disordered proteins Zsuzsanna Dosztányi MTA-ELTE...
![Page 1: PART II. Prediction of functional regions within disordered proteins Zsuzsanna Dosztányi MTA-ELTE Momentum Bioinformatics Group Department of Biochemistry.](https://reader035.fdocuments.net/reader035/viewer/2022062321/56649eac5503460f94bb345e/html5/thumbnails/1.jpg)
PART II.PART II.Prediction of functional Prediction of functional regions within disordered regions within disordered proteinsproteins
Zsuzsanna DosztányiMTA-ELTE Momentum Bioinformatics GroupDepartment of Biochemistry Eotvos Lorand University, Budapest, [email protected]
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Protein disorder is prevalent
20
40
60
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LD
R (
40<
) p
rote
in, %
kingdom
B
A
E
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Protein disorder is functional
Xie H et al. J Proteome Res. 2007, 6, 1882-1898
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Protein disorder is important
Prion protein Prion disease
CFTR Cystic fibrosis
Alzheimer’s
-synuclein Parkinson’s
p53, BRCA1 cancer
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Functions of intrinsically disordered proteins
I Entropic chains
II Linkers
III Molecular recognition
IV Protein modifications (e.g. phosphorylation)
V Assembly of large multiprotein complexes
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Interactions of IDPsComplex between p53 and MDM2
Coupled folding and binding
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Interactions of proteins
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Interactions of proteins
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Coupled folding and binding
Functional advantages
Weak transient, yet specific interactions Post-translational modifications Flexible binding regions that can overlap Evolutionary plasticity
SignalingRegulation
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Coupled folding and binding Experimental difficulties
Highly flexible Weak interactions Short half-life
Complexes of IDPs in the PDB: ~ 200 Known instances: ~ 2,000 Estimated number of such interactions in the
human proteome: ~ 100,000
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Interactions of IDPs
F19, W23 and L26
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p27
Cyclin-dependent kinase (Cdk) inhibitor, p27Kip1 (p27) Cell cycle regulation Binds to cdk-cyclin komplex and inhibitis their activity Fully disordered protein
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p27
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p27
Partial unfolding enables the phosphorylation of Tyr88, starting a series of signaling events that leads to the beginning of S phase.
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Prediction of functional regions within IDPs
Disordered binding regions (ANCHOR) Linear motifs (ELM, SlimPred) Morfs (Morfpred)
Specific conservation pattern
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Disordered protein complexes
Complex between p53 and MDM2
• Interaction sites are usually linear (consist of only 1 part)
• enrichment of interaction prone amino acids
Sequence
Binding sites
No need for structure, binding sites can be
predicted from sequence alone
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Prediction of disordered binding regions – ANCHOR
What discriminates disordered binding regions? A cannot form enough favorable interactions with their
sequential environment It is favorable for them to interact with a globular protein
Based on simplified physical model Based on an energy estimation method using statistical
potentials Captures sequential context
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ANCHOR
Human p53 C –terminal region
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ANCHOR and linear motifsNCOA2 transcription co-activator
The regions between 600-800 is disordered Contains 3 receptor binding motifs: xLxxLLx (LIG_NRBOX)
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LMs and Disordered Binding Regions
Linear motifs and disordered binding regions often overlap
Complementary approaches
Prediction of disordered binding regions can help to increase likelihood of true instances
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LMs and Disordered Binding Regions
Linear motifs and disordered binding regions often overlap
Complementary approaches
Prediction of disordered binding regions can help to increase likelihood of true instances
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Machine learning approaches
SlimPred: trained on ELM database
Morfpred: trained on short chains in complex
Very small datasets
Negative datasets
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Conservation
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Conservation patterns of linear motifs
No evolutionary constraints to keep the structure Strong constraints on functional site
Island-like conservation
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SlimPrints
Generates sequence alignments of orthologous sequences
Relative conservation score per position Filters out less reliable regions Fails if sequences are too divergent, or too similar http://bioware.ucd.ie/slimprints.html.