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Abstract
BackgroundIt is often the case that mammalian genes are alternatively spliced; the resulting alternate transcripts often encode protein isoforms that differ in amino acid sequences. Changes among the protein isoforms can alter the cellular properties of proteins. The effect can range from a subtle modulation to a complete loss of function.Results(i) We examined human splice-mediated protein isoforms (as extracted from a manually curated data set, and from a computationally predicted data set) for differences in the annotation for protein signatures (Pfam domains and PRINTS fingerprints) and we characterized the differences & their effects on protein functionalities. An important question addressed relates to the extent of protein isoforms that may lack any known function in the cell. (ii) We present a database that reports differences in protein signatures among human splice-mediated protein isoform sequences.Conclusion(i) Characterization: The work points to distinct sets of alternatively spliced genes with varying degrees of annotation for the splice-mediated protein isoforms. Protein molecular functions seen to be often affected are those that relate to: binding, catalytic, transcription regulation, structural molecule, transporter, motor, and antioxidant; and the processes that are often affected are nucleic acid binding, signal transduction, and protein-protein interactions. Signatures are often included/excluded and truncated in length among protein isoforms; truncation is seen as the predominant type of change. Analysis points to the following novel aspects: (a) Analysis using data from the manually curated Vega indicates that one in 8.9 genes can lead to a protein isoform of no "known" function; and one in 18 expressed protein isoforms can be such an "orphan" isoform; the corresponding numbers as seen with computationally predicted ASD data set are: one in 4.9 genes and one in 9.8 isoforms. (b) When swapping of signatures occurs, it is often between those of same functional classifications. (c) Pfam domains can occur in varying lengths, and PRINTS fingerprints can occur with varying number of constituent motifs among isoforms – since such a variation is seen in large number of genes, it could be a general mechanism to modulate protein function. (ii) Data: The reported resource (at ) provides the community ability to access data on splice-mediated protein isoforms (with value-added annotation such as association with diseases) through changes in protein signatures.
Highlights
It is often the case that mammalian genes are alternatively spliced; the resulting alternate transcripts often encode protein isoforms that differ in amino acid sequences
An example that illustrates fine modulation can be seen among the isoforms of AT1: the protein product of human AT1 gene binds to angiogenesis II (Ang II) hormone peptide; four transcript isoforms have been identified for hAT1 gene that essentially leads to two protein isoforms differing from one another by a 32-amino acid extension at the N-terminal; the shorter isoform has higher affinity to the hormone peptide than the longer isoform; the potency of the Ang II response varies depending on the relative abundance of these two protein isoforms [13]
Examining the protein isoforms for changes in signatures For every gene, we firstly identified a reference protein which is the longest of the expressed protein isoforms; choosing the longest protein as reference is justified by an observation that in only < 5% instances of genes, the longest peptide had fewer Database of Protein Family Domain signatures (Pfam) domains or Database of protein motif fingerprints (PRINTS) signatures than the other isoforms
Summary
It is often the case that mammalian genes are alternatively spliced; the resulting alternate transcripts often encode protein isoforms that differ in amino acid sequences. Alternative splicing leads to variants of proteins with diverse changes that can range from profound effects to fine modulation of protein activity [11]. An example that illustrates fine modulation can be seen among the isoforms of AT1: the protein product of human AT1 (angiotensin II type 1 receptor) gene binds to angiogenesis II (Ang II) hormone peptide; four transcript isoforms have been identified for hAT1 gene that essentially leads to two protein isoforms differing from one another by a 32-amino acid extension at the N-terminal; the shorter isoform has higher affinity to the hormone peptide than the longer isoform; the potency of the Ang II response varies depending on the relative abundance of these two protein isoforms [13]
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