Tissue Usage Preference and Intrinsically Disordered Region Remodeling of Alternative Splicing Derived Proteoforms in the Heart

A computational analysis of mass spectrometry data was
performed
to uncover alternative splicing derived protein variants across chambers
of the human heart. Evidence for 216 non-canonical isoforms was apparent
in the atrium and the ventricle, including 52 isoforms not documented
on SwissProt and recovered using an RNA sequencing derived database.
Among non-canonical isoforms, 29 show signs of regulation based on
statistically significant preferences in tissue usage, including a
ventricular enriched protein isoform of tensin-1 (TNS1) and an atrium-enriched
PDZ and LIM Domain 3 (PDLIM3) isoform 2 (PDLIM3-2/ALP-H). Examined
variant regions that differ between alternative and canonical isoforms
are highly enriched with intrinsically disordered regions. Moreover,
over two-thirds of such regions are predicted to function in protein
binding and RNA binding. The analysis here lends further credence
to the notion that alternative splicing diversifies the proteome by
rewiring intrinsically disordered regions, which are increasingly
recognized to play important roles in the generation of biological
function from protein sequences.