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Modeling post‐translational modifications and cancer‐associated mutations that impact the heterochromatin protein 1α‐importin α heterodimers
Author(s) -
Zimmermann Michael T.,
Williams Monique M.,
Klee Eric W.,
Lomberk Gwen A.,
Urrutia Raul
Publication year - 2019
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.25752
Subject(s) - heterochromatin , heterochromatin protein 1 , biology , computational biology , linker , nuclear transport , protein–protein interaction , importin , microbiology and biotechnology , chemistry , cell nucleus , genetics , nucleus , chromatin , gene , computer science , operating system
Heterochromatin protein 1α (HP1α) is a protein that mediates cancer‐associated processes in the cell nucleus. Proteomic experiments, reported here, demonstrate that HP1α complexes with importin α (IMPα), a protein necessary for its nuclear transport. This data is congruent with Simple Linear Motif (SLiM) analyses that identify an IMPα‐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 IMPα‐HP1α complex and investigate the impact of phosphorylation and genomic variants on their interaction. We demonstrate that phosphorylation of the HP1α linker likely regulates its association with IMPα, which has implications for HP1α access to the nucleus, where it functions. Cancer‐associated genomic variants do not abolish the interaction of HP1α but instead lead to rearrangements where the variant proteins maintain interaction with IMPα, but with less specificity. Combined, this new mechanistic insight bears biochemical, cell biological, and biomedical relevance.