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

Michael T. Zimmermann, Monique M. Williams, Eric W Klee, Gwen A. Lomberk, Raul Urrutia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalProteins: Structure, Function and Bioinformatics
DOIs
StatePublished - Jan 1 2019

Fingerprint

Karyopherins
Post Translational Protein Processing
Mutation
Neoplasms
Phosphorylation
Proteins
Molecular modeling
Cell Nucleus Active Transport
Molecular Dynamics Simulation
Cell Nucleus
Proteomics
Molecular dynamics
heterochromatin-specific nonhistone chromosomal protein HP-1
Cells
Association reactions
Computer simulation

Keywords

  • cancer
  • CBX5
  • functional genomics
  • HP1α
  • molecular modeling

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

Cite this

Modeling post-translational modifications and cancer-associated mutations that impact the heterochromatin protein 1α-importin α heterodimers. / Zimmermann, Michael T.; Williams, Monique M.; Klee, Eric W; Lomberk, Gwen A.; Urrutia, Raul.

In: Proteins: Structure, Function and Bioinformatics, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Urrutia, Raul

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