Formation of a structurally-stable conformation by the intrinsically disordered MYC:TRRAP complex

• Published in: PloS one Vol. 14; no. 12; p. e0225784
• Main Authors: Feris, Edmond J, Hinds, John W, Cole, Michael D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.12.2019; Public Library of Science (PLoS)
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Aprotinin; Biochemistry; Biology; Biology and Life Sciences; Cancer; Cell cycle; Cofactors; Cotton; Cotton, Norris; Deoxyribonucleic acid; DNA; Ethylene Glycol - pharmacology; Gene expression; HEK293 Cells; Homology; Humans; Intrinsically Disordered Proteins - chemistry; Kinases; Lung cancer; Medicine and Health Sciences; Mutation; Myc protein; Nuclear Proteins - chemistry; Peptides; Physical Sciences; Protein Binding - drug effects; Protein Conformation; Protein interaction; Protein Stability; Protein-protein interactions; Proteins; Proto-Oncogene Proteins c-myc - chemistry; Proton Magnetic Resonance Spectroscopy; Transcription factors; Tumors; Lebanon; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0225784

Our primary goal is to therapeutically target the oncogenic transcription factor MYC to stop tumor growth and cancer progression. Here, we report aspects of the biophysical states of the MYC protein and its interaction with one of the best-characterized MYC cofactors, TRansactivation/tRansformation-domain Associated Protein (TRRAP). The MYC:TRRAP interaction is critical for MYC function in promoting cancer. The interaction between MYC and TRRAP occurs at a precise region in the MYC protein, called MYC Homology Box 2 (MB2), which is central to the MYC transactivation domain (TAD). Although the MYC TAD is inherently disordered, this report suggests that MB2 may acquire a defined structure when complexed with TRRAP which could be exploited for the investigation of inhibitors of MYC function by preventing this protein-protein interaction (PPI). The MYC TAD, and in particular the MB2 motif, is unique and invariant in evolution, suggesting that MB2 is an ideal site for inhibiting MYC function.