Role of short linear protein motifs in Human diseases
Intrinsically disordered proteins (IDPs) are natively unfolded and lack a well-defined 3D structure under physiological conditions (Tompa 2009). Role of IDPs in cellular signalling and regulation is reflected in their association with human diseases. IDRs are common in proteins associated with human disease genes (Midic et al. 2008). Mutations in IDRs are thought to be causal in mis-signalling/mis-regulation based diseases because such mutations may disrupt the function of short linear motifs (SLiMs), which are the functional modules involved in mediating interactions of IDPs with multiple binding partners (Tompa, 2009). SLiMs are enriched within IDRs. They are involved in key cellular processes including signalling and regulation. They are mostly 3-10 residues long and typically 2-5 residues are essential for the function (Davey et al., 2011). Even a single amino acid substitution may impair the function of a motif. In fact, mutations that delete/create SLiMs have been previously linked to diseases. In this study I used 3 datasets of single amino-acid polymorphisms (SAPs): 1) Disease-associated SAPs annotated by UniProt (UniProt Consortium, 2012) by curating OMIM (McKusick, 1998) database (OMIM variants) 2) SAPs in cancer, annotated by COSMIC (Forbes et al. 2011) (COSMIC variants) 3) Common SAPs annotated by 1000GP (1000GP variants) (1000 Genomes Project Consortium, 2010). I looked for enrichment/depletion of disease-associated/common SAPs in SLiMs to emphasize importance of the link between SLiMs and diseases. Moreover, I constructed SLiM mediated interaction networks and looked at the distribution of the average number of interactions that a SAP could impact in SLiM mediated interactions. Finally, I made a literature survey of SAPs that impair functions of SLiMs and lead to diseases.
"Bora did his undergraduate studies in Biological Sciences and Bioengineering program of Sabanci University. He worked with Ugur Sezerman on ‘protein structure prediction’ and ‘structural motif finding’. Later, I was accepted to the CIHR/MSFHR Bioinformatics Graduate Training Program in Vancouver/Canada.There he worked in various labs on various projects including ‘transcriptome analysis’ (with Inanc Birol and Cenk Sahinalp), ‘microRNA target gene prediction’ (with Marco Marra) and ‘Comparative genomics analysis in Caenorhabditis species’ (with Nansheng Chen). After defending his M.Sc. thesis, Hemoved to Heidelberg-Germany to start my doctoral studies in the European Molecular Biology Laboratory. Since then,he has been working with Toby Gibson in the Structural & Computational Biology Unit. His main project is the analysis of ‘Short Linear Motifs’ and their association to human diseases."