Spatial Organization of Biological Fuctions | BPS Thematic Meeting

Spatial Organization of Biological Functions Meeting

Wednesday Speaker Abstracts

ALTERNATIVE ISOFORM SWITCHING REWIRES SPATIAL ORGANIZATION OF PROTEIN FUNCTION IN CANCER Kiruthiga Shankar Kumar 1 ; Dr.Naga Bhushana Rao Karampudi 1 ; 1 SRM University AP, Biological Sciences, Guntur, India Alternative splicing enables the production of protein isoforms with distinct structural and functional properties. In cancer, aberrant splicing frequently results in the expression of non canonical isoforms that differ from canonical forms in domain composition, intrinsic disorder, localization signals, and interaction profiles potentially altering their spatial organization within the cell. In this study, we investigated how isoform switching contributes to the spatial reprogramming of protein function in cancer. Isoform-level transcriptome data from normal and tumor tissues were integrated with structural feature predictions, including intrinsic disorder (IUPred2A), signal peptides (SignalP), aggregation-prone motifs (TANGO, PASTA), and domain architecture (Pfam). Using machine learning classifiers, we prioritized isoforms with significant structural and functional divergence. We found that cancer-enriched isoforms are significantly more disordered and frequently gain or lose critical features such as transmembrane regions, signal sequences, or aggregation-prone segments. These changes are predicted to impact protein folding, localization, and phase separation. Case studies of EGFR and FGFR2 revealed loss of membrane-associated domains and gain of aggregation-prone regions in tumor-specific isoforms, suggesting disrupted spatial regulation and signaling. Our results support a model in which isoform switching serves as a mechanism to reorganize the spatial distribution of proteins in cancer, affecting both molecular interactions and subcellular localization. This work highlights the importance of integrating expression data with biophysical features to uncover spatially regulated alterations in cancer biology.

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