rob russell cell networks university of heidelberg
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Interactions and Modules: the how and why of molecular interactions. Rob Russell Cell Networks University of Heidelberg. Proteins are modular. - PowerPoint PPT PresentationTRANSCRIPT
Russell Group, Protein Evolution
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Rob RussellCell Networks
University of Heidelberg
Interactions and Modules: the how and why of molecular
interactions
Russell Group, Protein Evolution
_________ ____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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“Low sequence complexity”(Linker regions? Flexible? Junk?
Domains on a sequence
Signal peptide(secreted or membrane attached)
Transmembrane segment(crosses the membrane)
Tyrosine kinase (phosphorylates Tyr)
Immunoglobulin domains(bind ligands?)
SMART domain ‘bubblegram’ for human fibroblast growth factor (FGF) receptor 1(type P11362 into web site: smart.embl.de)
Russell Group, Protein Evolution
_________ ____Finding domains in a sequence
Russell Group, Protein Evolution
_________ ____A library of protein domains for signaling
Pawson & Nash, Science, 2003
Russell Group, Protein Evolution
_________ ____Domains assemble to form higher-order structures
Pawson & Nash, Science, 2003
Russell Group, Protein Evolution
_________ ____How proteins interact
Russell Group, Protein Evolution
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Protein Ahomology
homology
(e.g.) Two-hybrid interaction
Protein B
Protein C
Protein D
Modelling interactions by homology
X
Can we use the C/D structure to predict an interaction between A & B?
Russell Group, Protein Evolution
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Family A Family B?
Can structure help solve the specificity problem?
Russell Group, Protein Evolution
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Structure
Asp
Arg Asp
Phe
Phe
Phe
Interface pair potentials
+ +
- -
Side-chain to side-chain
Side-chain to main-chain
Alignments
InterPreTSInteraction Prediction through Tertiary Structure
Aloy & Russell, PNAS, 99, 5896, 2002.Aloy & Russell, Bioinformatics. 19, 161, 2003.
1tx4A PIVLRETVAYLQA-------HALTTE ...YFE7_YEAST PLIISSIFSYMDKIYPDLPNDKVR-T ...
1tx4B KLVIVGDGACGKTCLLIVNSKDQF-- ...RHO4_YEAST KIVVVGDGAVGKTCLLISYVQGTFPT ...
Score
Significance(Do RHO4 & YFE7 interact?)
Russell Group, Protein Evolution
_________ ____How proteins interact
Russell Group, Protein Evolution
_________ ____Domain peptide interactions
Recognition of ligands or targeting signals
Post-translational modifications
Russell Group, Protein Evolution
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3BP1_MOUSE/528-537 APTMPPPLPPPTN8_MOUSE/612-629 IPPPLPERTPSOS1_HUMAN/1149-1157 VPPPVPPRRRNCF1_HUMAN/359-390 SKPQPAVPPRPSAPEXE_YEAST/85-94 MPPTLPHRDWSH3-interacting motif PxxP
“instance”
“perpetrator”
“motif”
“victim”
Peptides interacting with a common domain often show a common pattern or motif usually 3-8 aas.
Linear motifs
Puntervol et al, NAR, 2003; www.elm.org (Eukaryotic Linear Motif DB)
Russell Group, Protein Evolution
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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.
Linear motifs versus domains
Russell Group, Protein Evolution
_________ ____Intrinsically unstructured or disordered proteins or protein fragments
Russell Group, Protein Evolution
_________ ____Disorder predictors (IUPred, RONN, DisORPred, etc)
Russell Group, Protein Evolution
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Neduva & Russell, Curr. Opin. Biotech, 2006
Linear motif mediated interactions are everywhere
Include motifs for:• Targeting – e.g. KDEL• Modifications – e.g. phosphorylation• Signaling – e.g. SH3About 200 are currently known, likely many more still to be discovered
Russell Group, Protein Evolution
_________ ____Finding peptides or linear motifs in a sequence
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
See: elm.eu.org