Khader Shameer1,3, Prasahant N. Shingate1, Manjunath, S.C.P.1, Karthika, M.1, Ganesan Pugalenthi2 and Ramanathan Sowdhamini1*
1 National Centre for Biological Sciences (TIFR), GKVK Campus, Bangalore, 560065, India
2 Laboratory of Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672
3 Division of Biomedical Informatics and Statistics & Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN 55905 USA
Protein oligomerization is a key biochemical step to perform the designated function of proteins. 3D domain swapping is a unique protein oligomerization phenomenon observed in a wide array of proteins involved in diverse functional roles. Apart from its biological role, 3D domain swapping was proposed as the mechanistic basis of several conformational diseases.
We have performed in-depth literature curation and structural bioinformatics analyses and developed a curated knowledgebase of proteins involved in 3D domain swapping called '3DSwap' (1). We captured information on hallmark features of 3D domain swapping phenomenon from the literature. For example: the presence of largely unstructured regions that connect two regions of swapped structures called 'hinge regions' and one or more structured segments called 'swapped regions' were observed in swapped proteins. Further, we have integrated the literature-curated information and structural bioinformatics pipeline to identify the boundaries of hinge and swapped regions in protein structures involved in swapping. We have also introduced several new concepts like 'secondary major interface' and an algorithm to find 'extent of swapping' for systematic exploration of swapping in protein structures. Functional and structural data annotations from databases like Conserved Domain Database, Gene Ontology, Pfam, Protein Data Bank and Structural Classification of Proteins were integrated in 3DSwap. The database offers convenient search and browse utilities in 3DSwap. Database can be searched using keywords targeting multiple annotation database and sequence similarity searches can be performed by using hinge sequence and swapped sequence target database. 3DSwap also offers tools for visualization of swapped segments and hinge regions, annotated topology diagrams, amino acid plots and structural features. Current version of 3DSwap has 293 protein structures in varying degree of resolutions (mean: 2.2 Ã…; SD: 0.46), which can be utilized for extensive analysis of 3D domain swapping. The sequence and structural data compiled in 3DSwap was used for developing machine learning algorithms to predict swapping (2,3), and survey of structural (4), functional and disease implications (5) of domain swapping. Availability of a large dataset on proteins involved in swapping may help to design studies that enable better understanding of various aspects of protein oligomerization, folding pathways and protein aggregation.
This work is supported by National Centre for Biological Sciences (TIFR) and Department of Biotechnology, India, to R.S. and K.S; Wellcome Trust, UK, Senior Research Fellowship to R.S.
1. Shameer, K., Shingate, P.N., Manjunath, S.C., Karthika, M., Pugalenthi, G. and Sowdhamini, R. (2011) 3DSwap: curated knowledgebase of proteins involved in 3D domain swapping. Database (Oxford), 2011, bar042.
2. Shameer, K., Pugalenthi, G., Kandaswamy, K.K. and Sowdhamini, R. (2011) 3dswap-pred: prediction of 3D domain swapping from protein sequence using Random Forest approach. Protein Pept Lett, 18, 1010-1020.
3. Shameer, K., Pugalenthi, G., Kandaswamy, K.K., Suganthan, P.N., Archunan, G. and Sowdhamini, R. (2010) Insights into Protein Sequence and Structure-Derived Features Mediating 3D Domain Swapping Mechanism using Support Vector Machine Based Approach. Bioinformatics and Biology Insights, 4, 10.
4. Shingate, P. and Sowdhamini, R. (2012) Analysis of domain-swapped oligomers reveals local sequence preferences and structural imprints at the linker regions and swapped interfaces. PLoS ONE, 7, e39305.
5. Shameer, K. and Sowdhamini, R. (2012) Functional repertoire, molecular pathways and diseases associated with 3D domain swapping in the human proteome. J Clin Bioinforma, 2, 8.