Download Russell Group, Protein Evolution

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Interactions and Modules: the how and
why of molecular interactions
Rob Russell
Cell Networks
University of Heidelberg
Russell Group, Protein Evolution
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Proteins are modular
Since the early 1970s it has been observed that protein structures are divided into
discrete elements or domains that appear to fold, function and evolve
independently.
Russell Group, Protein Evolution
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Domains on a sequence
“Low sequence complexity”
(Linker regions? Flexible? Junk?
Signal peptide
(secreted or membrane
attached)
Transmembrane segment
(crosses the membrane)
Immunoglobulin domains
(bind ligands?)
Russell Group, Protein Evolution
Tyrosine kinase
(phosphorylates Tyr)
SMART domain ‘bubblegram’ for human
fibroblast growth factor (FGF) receptor 1
(type P11362 into web site:
smart.embl.de)
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Finding domains in a sequence
Russell Group, Protein Evolution
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A library of protein domains for signaling
Russell Group, Protein Evolution
Pawson & Nash, Science, 2003
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Domains assemble
to form higher-order
structures
Russell Group, Protein Evolution
Pawson & Nash, Science, 2003
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How proteins interact
Russell Group, Protein Evolution
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Modelling interactions by homology
homology
Protein A
X
Protein C
(e.g.) Two-hybrid
interaction
Protein D
Protein B
homology
Can we use the C/D structure to predict an
interaction between A & B?
Russell Group, Protein Evolution
Can structure help_________
solve the
specificity problem?
Family A
Family B
?
Russell Group, Protein Evolution
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InterPreTS
Interaction Prediction through Tertiary Structure
Structure
Interface pair potentials
Phe
++
Asp
Phe
Asp
Arg
-Phe
Alignments
1tx4A
YFE7_YEAST
PIVLRETVAYLQA-------HALTTE ...
PLIISSIFSYMDKIYPDLPNDKVR-T ...
1tx4B
RHO4_YEAST
KLVIVGDGACGKTCLLIVNSKDQF-- ...
KIVVVGDGAVGKTCLLISYVQGTFPT ...
Score
Significance
(Do RHO4 & YFE7 interact?)
Side-chain to side-chain
Side-chain to main-chain
Russell Group, Protein Evolution
Aloy & Russell, PNAS, 99, 5896, 2002.
Aloy & Russell, Bioinformatics. 19, 161, 2003.
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How proteins interact
Russell Group, Protein Evolution
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Domain peptide interactions
Recognition of ligands
or targeting signals
Post-translational
modifications
Russell Group, Protein Evolution
Linear motifs
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Peptides interacting with a common domain often
show a common pattern or motif usually 3-8 aas.
3BP1_MOUSE/528-537
APTMPPPLPP
PTN8_MOUSE/612-629
IPPPLPERTP
“instance”
SOS1_HUMAN/1149-1157
VPPPVPPRRR
NCF1_HUMAN/359-390
SKPQPAVPPRPSA
PEXE_YEAST/85-94
MPPTLPHRDW
SH3-interacting motif
PxxP
“motif”
“perpetrator”
“victim”
Russell Group, Protein Evolution
Puntervol et al, NAR, 2003; www.elm.org (Eukaryotic Linear Motif DB)
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Linear motifs versus domains
Domains: large globular segments of the
proteome that fold into discrete structures and
belong in sequence families.
Linear motifs: small, non-globular segments that
do not adopt a regular structure, and aren’t
homologous to each other in the way domains
are.
Motifs lie in the disordered part of the proteome.
Russell Group, Protein Evolution
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Intrinsically unstructured or disordered
proteins or protein fragments
Russell Group, Protein Evolution
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Disorder predictors (IUPred, RONN,
DisORPred, etc)
Russell Group, Protein Evolution
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Linear motif mediated
interactions
are everywhere
Include motifs for:
• Targeting – e.g. KDEL
• Modifications – e.g. phosphorylation
• Signaling – e.g. SH3
About 200 are currently known, likely
many more still to be discovered
Russell Group, Protein Evolution
Neduva & Russell, Curr. Opin. Biotech, 2006
Finding peptides _________
or linear motifs
in a sequence
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See: elm.eu.org
Finding these modules much harder than for domains.
Domains are long (>30 AA) and belong to sequence families that help detect new family
members
Linear motifs are typically < 8 amino acids long and have simple patterns
e.g. PxxP will occur in most sequences randomly and these are not SH3 domains
Russell Group, Protein Evolution