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Structural systems biology: modelling protein interactions

Key Points

  • Much of systems biology aims to predict the behaviour of biological systems on the basis of the set of molecules involved. Understanding the interactions between these molecules is therefore crucial to such efforts.

  • A full understanding of how molecules interact comes only from three-dimensional structures, but structural biology is still difficult for complexes of two or more macromolecules. This makes the methods that are used to predict structural details for interactions of crucial importance.

  • The interactomes for Saccharomyces cerevisiae, Drosophila melanogaster, Caenorhabditis elegans, Helicobacter pylori, Escherichia coli and Homo sapiens that are available at present can be readily complemented by methods that predict interactions on the basis of genome context, expression patterns and using other data sources.

  • The molecular details of interactions can be predicted by protein docking, homology modelling, or identifying recurring interaction-sequence signatures, either a pair of domains or a domain and a short linear peptide.

  • Using these tools, it is possible to predict the structures of large molecular assemblies or the details of how cellular pathways operate.

  • Complementing the interactome with structural information will ultimately produce a more complete whole-cell framework at atomic-level detail, which will have a large impact on the study of biological systems.

Abstract

Much of systems biology aims to predict the behaviour of biological systems on the basis of the set of molecules involved. Understanding the interactions between these molecules is therefore crucial to such efforts. Although many thousands of interactions are known, precise molecular details are available for only a tiny fraction of them. The difficulties that are involved in experimentally determining atomic structures for interacting proteins make predictive methods essential for progress. Structural details can ultimately turn abstract system representations into models that more accurately reflect biological reality.

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Figure 1: Structural details of part of the fibroblast-growth-factor signalling pathway.
Figure 2: Moving from abstract networks to real cells.

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Acknowledgements

We thank T. Gibson (European Molecular Biology Laboratory (EMBL), Heidelberg, Germany), R. Jackson (University of Leeds, UK) and A. Bonvin (University of Utrecht, The Netherlands) for helpful discussions.

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Correspondence to Robert B. Russell.

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The authors declare no competing financial interests.

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DATABASES

Protein Data Bank

1BKD

1C17

1C1Y

1EVT

1FA0

1FFK

1FJT

1FMK

1GRI

1IRS

1N5Z

1PFM

1R17

FURTHER INFORMATION

BioCarta

BioCyc

ELM (The Eukaryotic Linear Motif resource for Functional Sites in Proteins)

HADDOCK (High Ambiguity Driven protein–protein DOCKing based on biochemical and/or biophysical information)

InterPReTS (Interaction Prediction through Tertiary Structure)

iSPOT (Sequence Prediction Of Target)

KEGG (Kyoto Encyclopedia of Genes and Genomes)

NetPhos 2.0 Server

PhosphoELM

Reactome

STKE (Signal Transduction Knowledge Environment)

STRING (Search Tool for the Retrieval of Interacting Genes/Proteins)

Glossary

Structural genomics

Initiatives to solve X-ray or NMR structures in a high-throughput manner. They are usually focused on a single organism, pathway or disease, or are aimed at providing a complete set of protein folds (by solving representative structures, on the basis of which all other structures can be modelled).

Homology modelling

A method of protein-structure prediction that uses a known structure as a modelling template for a homologue that has been identified on the basis of sequence similarity.

Interactome

The protein-interaction equivalent of the genome. It denotes the set of interactions that occur in an organism.

Chemical crosslinking

The process of chemically joining two molecules using a covalent bond. Chemical agents are used to determine near-neighbour relationships, to analyse protein structure, and to provide information on the distance between interacting molecules.

Chemical footprinting

A method that takes advantage of chemical labelling to study protein–protein and protein–DNA interactions, by identifying the exact residues or DNA signature to which a protein binds.

Protein arrays

Solid-phase, ligand-binding assays that use immobilized proteins on different surfaces (for example, glass or membranes). Bound proteins are normally identified using specific antibodies.

Fluorescence resonance energy transfer

(FRET). The process of energy transfer between two fluorophores, which can be used to measure protein interactions in vivo. It can be used to determine the distance between two molecules or between two attachment positions in a macromolecule.

Fluorescence cross-correlation spectroscopy

(FCCS). A technique that detects the synchronous movement of two biomolecules with different fluorescent labels. It can be applied to live cells.

Protein-fold recognition (or threading)

A method of protein-structure prediction that attempts to find a suitable template on which to model a protein of unknown structure regardless of any sequence similarity (because dissimilar sequences can adopt similar protein folds). The sequence being queried is fitted, or threaded, onto a library of known structures to find out which one is most compatible (as measured by various structural criteria — for example, how well hydrophobic residues are buried).

SH3 domain

(Src-homology-3 domain). A protein of about 50 amino acids that recognizes and binds to sequences that are rich in proline residues.

SH2 domain

(Src-homology-2 domain). A protein motif that recognizes and binds to tyrosine-phosphorylated sequences, and thereby has a key role in relaying cascades of signal transduction.

WW domain

A protein-interaction domain that is characterized by a pair of tryptophan residues that are 20–22 amino acids apart, and an invariant proline residue within a region of 40 amino acids. WW domains interact with proline-rich regions, including those containing phosphoserine or phosphothreonine.

PDZ domain

(postsynaptic-density protein of 95 kDa, Discs large, Zona occludens-1). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.

RAD51

The early steps of recombination involving homologous pairing and strand exchange are promoted by proteins of the RecA/RAD51 family of recombinases in all organisms. Human RAD51 is a relatively small protein, but it is functional as a long helical polymer that is made up of hundreds of monomers.

Exosome

A protein complex found in eukaryotes and archae that has 3′→5′ exonuclease activity and is involved in RNA processing and degradation.

Electron tomography

A structural technique that allows a single cell to be studied using cryo-freezing and by obtaining data using a series of tilt angles in the electron beam, such that a three-dimensional image can be reconstructed.

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Aloy, P., Russell, R. Structural systems biology: modelling protein interactions. Nat Rev Mol Cell Biol 7, 188–197 (2006). https://doi.org/10.1038/nrm1859

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