1. MitoInteractome : Mitochondrial Protein Interactome Database Rohit Reja (rohit@kribb.re.kr)rohit@kribb.re.kr Korean Bioinformation Center, Daejeon, Korea University of Science and Technology, Daejeon, Korea

2. Mitochondrial Proteins Mitochondrial proteins are proteins, which have their functionality in mitochondria. Genes encoding mitochondrial proteins : Nuclear and Mitochondrial. Implicated in various energy metabolism defects and neuro-degenerative diseases. Existing mitochondrial protein databases : Human Mitochondrial Protein Database, MitoProteome, MitoP. To gain in depth understanding of molecular functions and processes of mitochondria, it is essential to examine interactions among its proteins.

3. Protein-Protein Interaction (PPI) PPI refers to the association of protein molecules and the study of these associations from the perspective of biochemistry and networks. Functions : signal transduction, formation of protein complexes, enzyme catalysis. Significance : functional role in biological processes, diseases and basis for new drug development or therapeutic approaches. Existing databases of PPI : IntAct, DIP, BioGrid, String, and HPRD. PPI Network

4. MitoInteractome : Mitochondrial Protein Interactome database We present “MitoInteractome”, a consolidated multi-species database for mitochondrial proteins that integrates information relevant to functions, pathways, diseases, protein-protein interaction and physico-chemical properties. Motivation: To serve as a research tool for computationally finding interacting partners, studying mitochondrial diseases and performing pathway analysis. To serve as a model for comprehensive collection and organization of mitochondria specific data.

5. Flowchart for MitoInteractome construction

6. Flowchart for illustrating the filtering criteria of MitoInteractome

7. Prediction using PSIMAP  Protein Structural Interactome MAP (PSIMAP) is a global interaction map that describes domain-domain and protein-protein interaction information for known Protein Data Bank structures.  Structure based prediction method using ‘5 by 5 rule’*.  SCOP domains were assigned to mitochondrial protein dataset using BLAST with Identity 40%, sequence coverage 70% and e- value 10 -4.  36,359 interactions pairs predicted. ‘5 by 5 Rule’ *M. Schroeder et.al. (2003)

8. Prediction using PEIMAP  Protein Experimental Interaction MAP (PEIMAP) Principle:  Sequence based method using homologous interaction concept. PEIMAP Principle 23,973 interaction pairs predicted.

9. Data for developers  Information for users For every protein in the mitochondria, Mitointeractome contains : General protein information. (such as protein description, classification, physicochemical properties, and amino acid charge distribution ). Protein – Protein interaction information. Pathway Information. Disease information. SNP Information.

10. Search Interface

11. General protein information Function

12. Interaction viewer Interaction partners Protein-Protein interaction information

13. Visualization of interaction map

14. nsSNP effect SNP related Information

15. Pathway related information Pathway association

16. How is MitoInteractome standard? Quantity, Quality and Originality of Data. Quality of web interface. Comprehensive nature and not over specialized. High speed and secure access to public domain. Non Redundancy. (Ref: Alex Bateman. Nucleic Acids Research Editorial. Nucleic Acids Research 2007 35(Database issue):D1-D2; doi:10.1093/nar/gkl1051)

17. MitoInteractome case study: ‘Aging Network’ construction Studies in past have indicated the association of mitochondria with aging. Several neuro-degenerative disorders are progressive in nature with aging*. List of 42 distinct proteins were obtained from GO database and queried against MitoInteractome and IntAct for plausible interacting partners. The network had 2,527 nodes and 5,356 edges. * Harman et. al.(1972), Richter et al (1995), and Barja et. al. (2002),

18. 0.01 0.23 0.47 0.49 0.32 0.67 0.81 ‘Aging Network’ analysis

19. Strength of a node: A centrality measure - “Strength of a node” was introduced, which is defined as the sum of the weights of other nodes it is interacting with. Strength of a node in the present network would capture: 1) the size of its neighborhood 2) uniqueness of the neighborhood Proteins with higher strengths were observed to be involved in at least one aging-related disorder.

20. ‘Aging Network’

22. How is MitoInteractome unique? MitoInteractome provides protein-protein interaction information with graphical display. Upon discovery of a new mitochondrial protein, it can be queried using BLAST incorporated in MitoInteractome. Correlation of mitochondrial protein mutations with the nature of their impact. Specific pathway information to aid study of mitochondrial diseases.

23. Availability and requirements MitoInteractome can be accessed here: www.mitointeractome.kobic.kr Java version 1.5 or later will be required to view the predicted interactions.

24. Conclusions: Aid in increasing our understanding of the molecular functions and interaction networks of mitochondrial proteins Help in identifying new mitochondrial target proteins for experimental research using predicted protein-protein interaction information. Help in identifying biomarkers for diagnosis and new molecular targets for drug development related to mitochondrial disorders. Information stored in MitoInteractome can be used to construct other disease related sub-networks similar to ‘aging network’ shown here.

25. Q and A