Chapter 5. Conclusion
5.2 Future works
5.2.2 Combination of sequence-based and structure-based interolog mapping
Our laboratory has developed a concept “3D-domain interologs”4, 54. We will combine the sequence-based homologous PPIs with the structure-based method of interolog mapping. The detail of the concept of 3D-domain interologs is described as follows.
For studying the mechanisms of PPIs in multiple species, domain-domain interactions, which are regarded as key of PPIs, should be identified. As the rapid increasing of protein structures, to identify interacting domains from three-dimensional (3D) structural complexes is able to study domain-domain interactions. A known 3D structure of interacting proteins provides interacting domains and atomic details for thousands of direct physical interactions.
Based on considering interacting domain of interacting protein pair, we have proposed a concept “3D-domain interolog mapping” to improve the generalized interologs mapping. Two physical interacting-domain sequences of a 3D-dimer protein structure are used as the queries to identify its 3D-domain interolog candidates by searching on protein sequences of genomes by utilizing PSI-BLAST. The proteins with both significant sequence similarity and the same interacting domains are considered as 3D-domain homologs forming a homolog family. Here, we define as 3D-domain homologs as: (1) candidates of both alignments with a significant PSI-BLAST E-value (< 10-8); (2) candidates have 25% domain sequence identity in both sequences in the PSI-BLAST alignment; (3) candidates have 25% sequence identity in both sequences on contacted residues in the PSI-BLAST alignment. The 3D-domain interolog candidates are defined as the all protein pairs between two homolog families derived from two sequences of a structure 3D-dimer (Figure 20). We believe that 3D-domain interolog mapping is able to study
the evolution of the interacting domain through 3D-domain homologous family from multiple 3d-domain interolog mapping &
Generalized interolog mapping
ecTbetaR2 (interacting domain)
TGF beta (interacting domain) Pfam-B 73018
PKinase Pfam-B 211911
Activin_recp TGF_beta_GS
Figure 20. Architecture of 3D-domain interolog mapping. Human TGF-B3 and TGFBR-2 co-crystallize in PDB55. Four Zebrafish homologous proteins of Human TGF-B3 found are by PSIBLAST. Likewise, five Zebrafish proteins are homologous to Human TGFBR-2. Through generalized interologs mapping, all possible pairs between the two families are considered as the generalized interologs (show as black and green line with arrows). Moreover, we could find the interacting domains of TGF-B3－TGFBR-2 complex (TGF beta domain is showed as gray and ecTbetaR2 domain is shown as light green) by exploring the co-crystal structure. The pairs of proteins which contain these interacting domains are considered as 3D-domain interologs (show as green line with arrows).
Based on combination of homologous PPIs and 3D-domain interologs, we will develop a new scoring function to model protein interface. The scoring function is
E = Einteracting + Econsensus + Esimilarity
The scoring function is composed of interacting force (Einteracting), consensus of residues (Econsensus) and template similarity (Esimilarity). We have applied this function and 3D-domain interologs to measure the interaction changes during evolution and the effect of residue substitution on the binding interface.
Human Mouse Cow
Type 1 Type 2
Human Mouse
Cow
Interacting score >= threshold
Type 1 Type 2
Homologs Interacting protein pair
Homologs
Figure 21. Overview of mutation analysis in protein-protein interactions.
In comparison of biochemical networks across species, protein-protein interactions may be conserved or non-conserved. Figure 21 shows an overview of how we analyze the causes of a protein-protein interaction would keep or lose in different organisms. In our study, we have acquired a reliable threshold of E (= Einteracting+Econsensus+Esimilarity) to estimate that two proteins will interact with each other or not. The contacting residues of homologous proteins among organisms are colored by yellow and green.
In Figure 21, the protein-protein interaction exists in human and mouse (≥ threshold) but
not in cow (< threshold). This observation suggests that the mutation in human (colored red) may not disrupt the interaction (called Type 1 mutation), but the mutation in cow (colored blue) may cause the loss of this interaction (Type 2 mutation). This model could help us to perform large-scale analyses of changes in interacting modes and residues among multiple organisms.
These analyses will support us to understand the causes of conservation and diversity in protein-protein interaction networks.
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Appendix A
List of publications
Journal papers
1. Yang, J.-M. and Chen, C.-C. GEMDOCK: a generic evolutionary method for molecular docking. Proteins 55, 288-304 (2004). (Impact factor: 4.429)
2. Yao, Y.-Y., Shrestha K.L., Wu, Y.-J., Tasi H.-J., Chen, C.-C., Yang, J.-M., Ando, A., Cheng C.-Y. and Li, Y.-K. Structural simulation and protein engineering to convert an endo-chitosanase to an exo-chitosanase. Protein Engineering Design & Selection 21, 561-566 (2008). (Impact factor: 2.662)
3. Chen, C.-C., Lin, C.-Y., Lo, Y.-S. and Yang, J.-M. PPISearch: a web server for searching homologous protein-protein interactions across multiple species. Nucleic Acids Research 37:W376-W383 (2009). (Impact factor: 6.954)
Conference Papers
1. Huang J.-W., Chen, C.-C., Yang, J.-M. (2008) Identifying critical positions and rules of antigenic drift for influenza A/H3N2 viruses. The 2nd International Conference on Bioinformatics and Biomedical Engineering, pp. 249-252
Appendix B
Journal papers
Yang, J.-M. and Chen, C.-C. GEMDOCK: a generic evolutionary method for molecular docking. Proteins 55, 288-304 (2004).
Yao, Y.-Y., Shrestha K.L., Wu, Y.-J., Tasi H.-J., Chen, C., Yang, J.-M., Ando, A., Cheng C.-Y. and Li, C.-Y.-K. Structural simulation and protein engineering to convert an endo-chitosanase to an exo-chitosanase. Protein Engineering Design & Selection 21, 561-566 (2008).