Modeling post-translational modifications and cancer-associated mutations that impact the heterochromatin protein 1α-importin α heterodimers. Proteins 2019 Nov;87(11):904-916
Date
06/04/2019Pubmed ID
31152607Pubmed Central ID
PMC6790107DOI
10.1002/prot.25752Scopus ID
2-s2.0-85067403924 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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.
Author List
Zimmermann MT, Williams MM, Klee EW, Lomberk GA, Urrutia RAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinRaul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Associate Professor in the Data Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Amino Acid SequenceChromosomal Proteins, Non-Histone
Humans
Models, Molecular
Mutation
Neoplasms
Phosphorylation
Protein Binding
Protein Conformation
Protein Multimerization
Protein Processing, Post-Translational
Sequence Alignment
alpha Karyopherins
