Open AccessA Peptidomimetic Ligand Targeting the Chromodomain of MPP8 Reveals HRP2’s Association with the HUSH Complex
Author(s) -
Jarod Waybright,
Sarah E. Clinkscales,
Kimberly D. Barnash,
Gabrielle R. Budziszewski,
Justin M. Rectenwald,
Anna M. Chiarella,
Jacqueline Norris-Drouin,
Stephanie H. Cholensky,
Kenneth H. Pearce,
Laura E. Herring,
Robert K. McGinty,
Nathaniel A. Hathaway,
Lindsey I. James
Publication year - 2021
Publication title -
acs chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.899
H-Index - 111
eISSN - 1554-8937
pISSN - 1554-8929
DOI - 10.1021/acschembio.1c00429
Subject(s) - chromodomain , biology , bromodomain , histone , heterochromatin protein 1 , computational biology , peptidomimetic , context (archaeology) , epigenetics , chemistry , microbiology and biotechnology , biochemistry , genetics , chromatin , gene , heterochromatin , rna , peptide , helicase , paleontology
The interpretation of histone post-translational modifications (PTMs), specifically lysine methylation, by specific classes of "reader" proteins marks an important aspect of epigenetic control of gene expression. Methyl-lysine (Kme) readers often regulate gene expression patterns through the recognition of a specific Kme PTM while participating in or recruiting large protein complexes that contain enzymatic or chromatin remodeling activity. Understanding the composition of these Kme-reader-containing protein complexes can serve to further our understanding of the biological roles of Kme readers, while small molecule chemical tools can be valuable reagents in interrogating novel protein-protein interactions. Here, we describe our efforts to target the chromodomain of M-phase phosphoprotein 8 (MPP8), a member of the human silencing hub (HUSH) complex and a histone 3 lysine 9 trimethyl (H3K9me3) reader that is vital for heterochromatin formation and has specific roles in cancer metastasis. Utilizing a one-bead, one-compound (OBOC) combinatorial screening approach, we identified UNC5246, a peptidomimetic ligand capable of interacting with the MPP8 chromodomain in the context of the HUSH complex. Additionally, a biotinylated derivative of UNC5246 facilitated chemoproteomics studies which revealed hepatoma-derived growth factor-related protein 2 (HRP2) as a novel protein associated with MPP8. HRP2 was further shown to colocalize with MPP8 at the E-cadherin gene locus, suggesting a possible role in cancer cell plasticity.