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Understanding the Formation of the MCT‐1:DenR Complex, a Translational Enhancer for Lymphoma Survival
Author(s) -
Stowe Sean,
Cavalier Michael,
GodoyRuiz Raquel,
Varney Kristen,
Wilder Paul,
Gartenhaus Ronald,
Weber David
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.883.8
Subject(s) - eukaryotic translation , guanosine , enhancer , dimer , initiation factor , biology , cancer research , microbiology and biotechnology , chemistry , computational biology , translation (biology) , genetics , gene expression , gene , messenger rna , organic chemistry
Over the last the decade, our understanding of the role that translational enhancer proteins play in the increased occurrence of non‐Hodgkin lymphoma relapse and the development of drug resistant phenotypes has drastically increased. One such enhancer system is the MCT‐1:DenR complex. Identified due their high expression levels in human lymphomas, this complex has been shown to be directly involved in translation initiation and ribosomal recycling for transcripts containing serial 5'‐uORFs, leading to increased cell proliferation and anti‐apoptotic phenotypes. Through the combination of two RNA‐binding domains, a PUA domain from MCT‐1 and a SUI‐1 domain from DenR, the complex is believed to be anchored at the 7‐methyl guanosine cap and to direct the reassociation of the 43S initiation complex at AUG start codons, acting as a guide to bypass the uORFs. This study has been focused on the characterization of the complex structure and formation thermodynamics via a combination of NMR, X‐ray crystallography, and ITC. In particular, attention was paid to the conformational changes in the loosely ordered N‐terminal domain of DenR induced by dimer formation. Ultimately, the information gained from this study will be used to evaluate a library of perturbagens that interfere with dimer formation and the development of MCT‐1 driven anti‐apoptotic phenotypes. Research Support: NIH R01‐GM58888, R01‐CA107331, T32‐AR07592, P41‐GM103403, and P41‐GM103393