From Protein Structure to Function with Bioinformatics.pdf

12 Prediction of Protein Function from Theoretical Models 307Fig. 12.2 Modelling-based prediction of protein-protein interactions. A pipeline based on comparativemodelling of protein complexes (Davis et al. 2008) was able to use the structure ofcathepsin A in complex with stefin A (PDB code 1nb3; (a) to infer a probable interaction betweenfalcipain-2 and cystatin, as confirmed by crystallography (PDB code 1yvb; (b) enzymes are shownabove, and inhibitors below, in each paneltime to be a nucleic acid binding protein, a prediction strongly supported by theresemblance of its ab initio model to structures in a SCOP superfamily containingdiverse nucleic acid binding proteins. The accuracy of the model is revealed nowby two unpublished Structural Genomics outputs (1yez and 1yvc). An example offunction prediction for a completely uncharacterised protein was made for Domainof Unknown Function 37 (PF01809). Its model matched the structure of NK-lysina haemolytic protein expressed in natural killer T-cells. Although the structure ofPF01809 proteins remains unknown, the Pfam database at the time of writingreports unpublished evidence that a member from Aeromonas hydrophila indeedhas haemolytic activity.Interestingly, an ab initio model need not match a known fold exactly in orderto offer clues to function; the broad structural class of the model may sometimes besuggestive. An example of this is the model produced for a mucin-binding domain(Bumbaca et al. 2007). The favoured model contained a β-sandwich fold, of thekind strongly associated with carbohydrate binding. At the time of publication, halfthe families of carbohydrate-binding domains of known structure folded intoβ-sandwich structures of some kind. This would be consistent with the domainbinding to the carbohydrate component, rather than a protein part, of its target, thehighly glycosylated mucin. Furthermore, the ab initio model contained threesolvent-exposed aromatic residues of the kind commonly associated with carbohydratebinding (Quiocho and Vyas 1999).