Most protein domains exist as variants with distinct functions across cells, tissues and diseases.

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. Here, I show that most human protein domains exist as multiple distinct variants termed 'domain isotypes'. Domain isotypes are used in a cell, tissue and disease-specific manner and have surprisingly different 3D structures. Accordingly, domain isotypes, compared to each other, modulate or abolish the functionality of protein domains. These 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 literature indicating we need to transition to an isoform-centric research paradigm.