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Russell Group, Protein Evolution _________ ____ Rob Russell Cell Networks University of Heidelberg Interactions and Modules: the how and why of molecular interactions
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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.
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Russell Group, Protein Evolution _________ ____ “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)
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Russell Group, Protein Evolution _________ ____ Finding domains in a sequence
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Russell Group, Protein Evolution _________ ____ A library of protein domains for signaling Pawson & Nash, Science, 2003
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Russell Group, Protein Evolution _________ ____ Domains assemble to form higher-order structures Pawson & Nash, Science, 2003
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Russell Group, Protein Evolution _________ ____ How proteins interact
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Russell Group, Protein Evolution _________ ____ Protein A 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?
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Russell Group, Protein Evolution _________ ____ Family AFamily B ? Can structure help solve the specificity problem?
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Russell Group, Protein Evolution _________ ____ Structure Asp Arg Asp Phe Interface pair potentials + - Side-chain to side-chain Side-chain to main-chain Alignments InterPreTS Interaction 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?)
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Russell Group, Protein Evolution _________ ____ How proteins interact
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Russell Group, Protein Evolution _________ ____ Domain peptide interactions Recognition of ligands or targeting signals Post-translational modifications
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Russell Group, Protein Evolution _________ ____ 3BP1_MOUSE/528-537 APTMPPPLPP PTN8_MOUSE/612-629 IPPPLPERTP SOS1_HUMAN/1149-1157 VPPPVPPRRR NCF1_HUMAN/359-390 SKPQPAVPPRPSA PEXE_YEAST/85-94 MPPTLPHRDW SH3-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)
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Russell Group, Protein Evolution _________ ____ 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
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Russell Group, Protein Evolution _________ ____ Intrinsically unstructured or disordered proteins or protein fragments
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Russell Group, Protein Evolution _________ ____ Disorder predictors (IUPred, RONN, DisORPred, etc)
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Russell Group, Protein Evolution _________ ____ 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. SH3 About 200 are currently known, likely many more still to be discovered
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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
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