Disentangling the CHAOS of intrinsic disorder in human proteins

Most proteins consist of both folded domains and Intrinsically Disordered Regions (IDRs). However, the widespread occurrence of intrinsic disorder in human proteins, along with its characteristics, is often overlooked by the broader communities of structural and molecular biologists. Building on the MobiDB database of intrinsically disorder in proteins, here we develop a comprehensive dataset ( C omprehensive analysis of H uman proteins A nd their dis O rdered S egments (CHAOS)). We implement empirical internally consistent definitions of what constitutes a disordered region, annotate general characteristics such as cellular location, essentiality, and post-translational modifications, and cross-reference to structure predictions from AlphaFold. Most proteins contain at least one disordered region, predominantly located at the protein termini. IDRs are less hydrophobic and are enriched in post-translational modifications compared to non-IDRs. Additionally, we discovered that proteins residing in different cellular locations possess distinct disorder profiles. Finally, the predicted AlphaFold models of proteins in CHAOS suggest that while protein disorder may be intrinsic, it does not have to be extrinsic. Hereby we enhance the visibility and understanding of intrinsic disorder in human proteins.