Computational analysis of regulatory regions in human protein kinases

Eukaryotic proteins often feature modular domain structures comprising globular domains that are connected by linker regions and intrinsically disordered regions that may contain important functional motifs. The intramolecular interactions of globular domains and nonglobular regions can play critical roles in different aspects of protein function. However, studying these interactions and their regulatory roles can be challenging due to the flexibility of nonglobular regions, the long insertions separating interacting modules, and the transient nature of some interactions. Obtaining the experimental structures of multiple domains and functional regions is more difficult than determining the structures of individual globular domains. High‐quality structural models generated by AlphaFold offer a unique opportunity to study intramolecular interactions in eukaryotic proteins. In this study, we systematically explored intramolecular interactions between human protein kinase domains (KDs) and potential regulatory regions, including globular domains, N‐ and C‐terminal tails, long insertions, and distal nonglobular regions. Our analysis identified intramolecular interactions between human KDs and 35 different types of globular domains, exhibiting a variety of interaction modes that could contribute to orthosteric or allosteric regulation of kinase activity. We also identified prevalent interactions between human KDs and their flanking regions (N‐ and C‐terminal tails). These interactions exhibit group‐specific characteristics and can vary within each specific kinase group. Although long‐range interactions between KDs and nonglobular regions are relatively rare, structural details of these interactions offer new insights into the regulation mechanisms of several kinases, such as HASPIN, MAPK7, MAPK15, and SIK1B.