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Identification and characterization of DSPIa, a novel isoform of human desmoplakin
Rita M Cabral1, Hong Wan, Clare L Cole
1Centre for Cutaneous Research, Blizard Institute of Cell and Molecular Science, University of London, London, UK.
Abstract:
Desmoplakin is a ubiquitous component of desmosomes and desmosome-like structures, such as the cardiomyocyte area composita. Two major isoforms, desmoplakin I (DSPI) and desmoplakin II (DSPII) are encoded by alternative mRNA transcripts differentially spliced from the same gene. The resulting proteins are identical in amino acid sequence with the exception that DSPII contains only one third of the central alpha-helical rod domain present in DSPI. Here we describe a novel minor isoform of desmoplakin that is also produced by alternative splicing of the desmoplakin gene and that we name desmoplakin Ia (DSPIa). DSPIa is an alternatively spliced DSPI mRNA with a unique splice donor site that is 90% homologous to and downstream of the DSPII specific donor. The resulting DSPIa mRNA is in-frame and encodes a protein that has a central alpha-helical rod domain of intermediate size and that is 156 amino acids larger than DSPII and 443 amino acids smaller than DSPI. We demonstrate, through recombinant expression and short interfering RNA knockdown, that the DSPIa protein is readily detectable, albeit at substantially lower levels than the dominant isoforms, DSPI and DSPII. DSPIa mRNA has a similar tissue distribution to that of DSPI and of DSPII.
Insights
Researchers discovered a new desmoplakin isoform, desmoplakin Ia (DSPIa), generated by alternative splicing. This minor protein isoform exhibits intermediate-sized central rod domains and is detectable in tissues alongside major desmoplakin forms.
Area of Science:
- Molecular Biology
- Cell Biology
- Protein Isoforms
Background:
- Desmoplakin is a key structural protein in desmosomes and cardiomyocyte area composita.
- Two major desmoplakin isoforms, DSPI and DSPII, arise from alternative mRNA splicing.
- These isoforms differ in the size of their central alpha-helical rod domain.
Purpose of the Study:
- To identify and characterize novel alternatively spliced isoforms of desmoplakin.
- To investigate the expression and properties of a newly discovered desmoplakin isoform, DSPIa.
Main Methods:
- Analysis of alternative mRNA splicing of the desmoplakin gene.
- Recombinant protein expression to study desmoplakin Ia (DSPIa).
- Short interfering RNA (siRNA) knockdown to assess DSPIa protein levels.
Main Results:
- A novel desmoplakin isoform, desmoplakin Ia (DSPIa), was identified, produced by alternative splicing.
- DSPIa mRNA utilizes a unique splice donor site, resulting in a protein with an intermediate-sized central rod domain.
- DSPIa protein is detectable, though at lower levels than DSPI and DSPII, with similar tissue distribution.
Conclusions:
- Alternative splicing of the desmoplakin gene generates at least three protein isoforms (DSPI, DSPII, and DSPIa).
- DSPIa represents a previously undescribed, minor desmoplakin isoform with distinct structural characteristics.
- The discovery of DSPIa expands our understanding of desmoplakin diversity and its role in cellular structures.
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