Book of Abstracts: Albany 2007
June 19-23 2007
Alternative Splicing and Intrinsic Disorder: Their Association and its Implications on Multicellular Complexity
Alternative splicing of pre-mRNA generates two or more protein isoforms from a single gene, thereby contributing to protein diversity in eukaryotes. Intrinsic disorder, that is, lack of an equilibrium three-dimensional structure, empowers protein for signaling, and regulation functions. Despite intensive efforts, an understanding of the protein structure-function implications of alternative splicing is still lacking. We hypothesize that mapping alternatively spliced segments to regions of intrinsic protein disorder enables functional and regulatory diversity while avoiding structural catastrophe. To test this hypothesis, we analyzed a set of differentially spliced genes encoding structurally characterized human proteins containing both structured and intrinsically disordered amino acid residues. We show that, in 81% of the examples, alternative splicing was associated with fully and partially disordered protein regions and concomitantly led to functional profiling. Alternative splicing was shown to occur predominantly in areas of pre-mRNA encoding for disordered regions in the corresponding proteins with very high significance (p-value < 10-18). Associating alternative splicing with protein disorder enables the highly abundant time-specific, tissue-specific and diverse modulation of protein function needed for cell differentiation, and for the evolution of multicellular organisms.
CCBB and School of Informatics, IUPUI