Modeling post-translational modifications and cancer-associated mutations that impact the heterochromatin protein 1α-importin α heterodimers

Heterochromatin protein 1 alpha (HP1 alpha) is a protein that mediates cancer-associated processes in the cell nucleus. Proteomic experiments, reported here, demonstrate that HP1 alpha complexes with importin alpha (IMP alpha), a protein necessary for its nuclear transport. This data is congruent with Simple Linear Motif (SLiM) analyses that identify an IMP alpha-binding motif within the linker that joins the two globular domains of this protein. Using molecular modeling and dynamics simulations, we develop a model of the IMP alpha-HP1 alpha complex and investigate the impact of phosphorylation and genomic variants on their interaction. We demonstrate that phosphorylation of the HP1 alpha linker likely regulates its association with IMP alpha, which has implications for HP1 alpha access to the nucleus, where it functions. Cancer-associated genomic variants do not abolish the interaction of HP1 alpha but instead lead to rearrangements where the variant proteins maintain interaction with IMP alpha, but with less specificity. Combined, this new mechanistic insight bears biochemical, cell biological, and biomedical relevance.