Convergent Alterations of a Protein Hub Produce Divergent Effects within a Binding Site

Abstract

Progress in tumor sequencing and cancer databases has created an enormous amount of information that scientists struggle to sift through. While several research groups have created computational methods to analyze these databases, much work still remains in distinguishing key implications of pathogenic mutations. Here, we describe an approach to identify and evaluate somatic cancer mutations of WD40 repeat protein 5 (WDR5), a chromatin-associated protein hub. This multitasking protein maintains the functional integrity of large multi-subunit enzymatic complexes of the six human SET1 methyltransferases. Remarkably, the somatic cancer mutations of WDR5 preferentially distribute within and around an essential cavity, which hosts the WDR5 interaction (Win) binding site. Hence, we assessed the real-time binding kinetics of the interactions of key clustered WDR5 mutants with the Win motif peptide ligands of the SET1 family members (SET1 _Win). Our measurements highlight that this subset of mutants exhibits divergent perturbations in the kinetics and strength of interactions not only relative to those of the native WDR5 but also among various SET1 _Win ligands. These outcomes could form a fundamental basis for future drug discovery and other developments in medical biotechnology.