Abstract
Background Protein domains are the active subunits that provide proteins with specific functions through precise three-dimensional structures. Such domains facilitate most protein functions, including molecular interactions and signal transduction. Currently, these protein domains are described and analyzed as invariable molecular building blocks with fixed functions.
Results I show that most human protein domains exist as multiple distinct variants that I term “domain isotypes”. Different domain isotypes are used in a cell, tissue, and disease-specific manner and have surprisingly different 3D structures. Accordingly, I find that domain isotypes, compared to each other, modulate or abolish the functionality of protein domains.
Conclusions My results challenge the current view of protein domains as invariable building blocks and have significant implications for both wet- and dry-lab workflows. The extensive use of protein domain isotypes within protein isoforms adds to the growing body of evidence suggesting that the sciences should move from the current gene-centric research paradigm toward an isoform-centric research paradigm.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Improved introduction and discussion based on community feedback.
