Russell Group, Protein Evolution

_________ ____

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