a basic understanding of intrinsically disordered proteins
DESCRIPTION
Intrinsically disordered proteins play important roles in signalling pathways in the body and are crucial to the the homeostasis of the body - when they malfunction, we malfunction! This is a bit of an introduction on these fascinating amino acid combinations.TRANSCRIPT
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Structural Understanding of
Intrinsically Disordered Proteins
Joe Passman
April 26, 2013
6/24/20131
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While I Have Your Attention…
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Overview
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Rise, Prevalence, and
Possible Roles of Disorder in
Proteins
Background
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Structure / Function Paradigm
Transcription
mRNA
mRNA
Translation
Peptide
3D Protein
Folding
Output
Nucleus
DNA
Splicing
Export
RNA
???
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Disorder Becomes Apparent
Early discovery
Bovine serum albumin binding sites (Karush,1950)
Later…
Rapid rise of genomic data (~1990)
Predictors of natural disordered regions (PONDRs)
Early proton NMR experiments (Daniels et al, 1978)
0
200
400
600
800
2013
2010
2007
2004
2001
1998
1995
1992
1989
1986
1983
1978
Nu
mb
er
of
Pu
bli
cati
on
s
Year
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Disorder, Disorder, (most)Everywhere!
Hosoda et al, 2011
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Why Did We Miss It?
Unobserved
Bias of experiment
Access to genomic data
limited before ~1990
Crystal structure
relatively uninformative
Ignored
Crystal structure artifacts
dismissed
Disorder thought to be an
artifact
Dyson & Wright, 2005
6/24/20138
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What is Disorder in Proteins?
Definition:
A protein that does not adopt a well-defined native
structure when isolated in solution under near-
physiological conditions (Eliezer, 2009)
2 types
Denatured state ensembles (DSEs)
Intrinsically disordered proteins (IDPs)
Vast and malleable configurational ensembles (CEs)
Charged
What can impact disorder?
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Why are IDPs Interesting?
Diverse Roles!
Regulatory
Homeostasis of signaling pathways
Translation/Transcription
Structural
Flexible Linkers
AND….. They can kill you.
Disease states
Cancer (lack of cell cycle regulation)
Brain (amyloid plaque formation)Lee et al, 2003
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Proposed Mechanisms
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Regulation
Folding upon binding
Highly specific / low affinity binding
Multiple interaction sites
Aggregation
Dyson & Wright, 2005Schärpf et al, 2001
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Background
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Structure
6/24/201313
107 residues (1799 atoms)
Positively charged side chains
Proportion of arginine to lysine: 22%
Structure Position Length
(residues)
Visual
Helix 4-10 7
Helix 12-20 9
Helix 23-25 3
Beta Strand 26-29 4
Beta Sheet
Alpha Helix
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Function
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Transient complex
Interacts with
RNA
RNA polymerase
End Result
Prevent termination of
transcription
Goldenberg, 2012
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More on Interaction with RNA
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Schärpf et al, 2001
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Regulatory function
Multiple interaction partners
Extensively unfolded in isolation
Flexible structure
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Background
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Questions, hypothesis, and
goals
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What Are We Trying to Address?
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Goldenberg, 2011
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Hypothesis/Expected Outcomes
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Goals
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Provide a set of atomistic properties
Quantify correspondence with macroscopic ensemble-
averaged experimental data
Develop reference point for crowding studies
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Context: Alzheimer’s Disease
NIH / National Institute on Aging
6/24/201321