The role of dancing duplexes in biology and disease

Across species, a common protein assembly arises: proteins containing structured domains separated by long intrinsically disordered regions, and dimerized through a self-association domain or through strong protein interactions. These systems are termed “IDP duplexes.” These flexible dimers have roles in diverse pathologies including development of cancer, viral infections, and neurodegenerative disease. Here we discuss the role of disorder in IDP duplexes with similar domain architectures that bind hub protein, LC8. LC8-binding IDP duplexes are categorized into three groups: IDP duplexes that contain a self-association domain that is extended by LC8 binding, IDP duplexes that have no self-association domain and are dimerized through binding several copies of LC8, and multivalent LC8-binders that also have a self-association domain. Additionally, we discuss non-LC8-binding IDP duplexes with similar domain organizations, including the Nucleocapsid protein of SARS-CoV-2. We propose that IDP duplexes have structural features that are essential in many biological processes and that improved understanding of their structure function relationship will provide new therapeutic opportunities.