Our group is interested in the relationships between protein three-dimensional (3D) structure, function and evolution. Current projects are focused in the following main areas.
Structure-based Systems Biology: Interaction & Complexes: Protein interaction networks are central to any understanding of cellular processes, and though many thousands are now known, few initiatives to uncover them pay much attention to one of the best sources of data available: complexes of known 3D structure. We thus study protein interactions by considering known 3D structures. We use 3D complexes to interrogate interactions identified by other methods (e.g. yeast two-hybrids) and to predict specific interactions within protein families. A major initiative in the group is related building as complete models as possible for all interacting proteins and complexes in a whole cell (Figure). This is particularly useful when combined with experimental methods like electron microscopy or interaction discovery. In this project we are very actively involved with the Boettcher, Bork and Serrano groups in the programme, in addition to Cellzome AG. It was recently selected as a funded Integrated Project 3D-Repertoire under EU FP6.
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Figure showing yeast complexes where 3D structures can be modelled (triangles or squares) and where interactions between them can be inferred by structure (black lines) and experimental methods (red lines). Colors show the broad functional class of the complex. More structural detail is shown for complexes related to transcription (bottom). See Aloy et al, Science, 2004 (below). |
Needles in Haystacks: Protein and DNA sequence motifs: A major current challenge in biology is to discover and understand short protein or nucleic acid stretches that mediate functional interactions. We currently search for new protein-peptide and microRNA target sequences in genomes using a variety of techniques. Both methods already make fascinating predictions of biological phenomena and provide a wealth of information for people working with such sequences experimentally.
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Schematic outlining our appraoch for finding protein linear motifs that mediate protein-protein interactions. Sets of proteins (A-F) sharing an interaction partner (X) are grouped and domains and homologous sequences are removed. We then search for 3-8 residue motifs that are over-represented in the remaining sequence, and score these by a binomial probability to give a ranked set of candiate motifs mediated the interaction with protein X. |
Function from Structure: Structural Genomics related projects: Thriving structural genomics projects, together with the growing pace of structural biology, now means that protein 3D structures can be known before function. These structures present fascinating challenges and require many new approaches to be most useful. We are currently developing methods for predicting function for structures by way of protein and small-molecules comparison. We also work on methods to predict regions in sequences most likely to be globular, which are aimed more at the target side of structural genomics (i.e. before structure determination begins).
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Example of searches that one can perform with PINTS. Here active site residues from LuxS (left) are compared to a database of other proteins to find the similarities shown on the right. See Stark & Russell, Nucl. Acids Res. (below). |
Structure prediction : We also applied our expertise in structure comparison and classification to the problem of assessing structure prediction accuracy during the CASP5 experiment (in the new fold/ab initio category. Information related to our assessment is available here, and in Aloy et al, Proteins, 53, 436-456, 2003 (CASP5 special issue) PubMed.
Protein evolution: For all of the above projects we try to consider what we can learn about how nature evolves protein structure & function. We are also interested in the origin of protein structures or fold, and the relationship between exons and three-dimensional structure.
Publications:
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