The intrinsically disordered TC-1 interacts with Chibby via regions with high helical propensity.
Thyroid cancer 1 (TC-1) is a 106-residue naturally disordered protein that has been found to associate with thyroid, gastric, and breast cancers. Recent studies showed that the protein functions as a positive regulator in the Wnt/beta-catenin signaling pathway, a pathway that is known to play essential roles in developmental processes and causes tumor formation when misregulated. By competing with beta-catenin for binding to Chibby (Cby), a conserved nuclear protein that antagonizes the beta-catenin-mediated transcriptions, TC-1 up-regulates a number of beta-catenin target genes that are known to be involved in the aggressive behavior of cancers. In order to gain a molecular understanding of the role TC-1 plays in regulating the Wnt/beta-catenin signaling pathway, detailed structural studies of the protein and its interaction with Cby are essential. In this work, we used nuclear magnetic resonance (NMR) spectroscopy to elucidate the structure of TC-1 and its interaction with Cby. Our results indicate that even though TC-1 is naturally disordered, the protein adopts fairly compact conformations under nondenaturing conditions. Chemical shift analysis and relaxation measurements show that three regions (D44-R53, K58-A64, and D73-T88) with high-helical propensity are present in the C-terminal portion of TC-1. Upon addition of Cby, significant broadening of resonance signals derived from these helical regions of TC-1 was observed. The result indicates that the intrinsically disordered TC-1 interacts with Cby via its transient helical structure.
Gall
Chris
C
Department of Biochemistry, University of Western Ontario, London, Canada.
Xu
Hanyu
H
Brickenden
Anne
A
Ai
Xuanjun
X
Choy
Wing Yiu
WY
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D015398:Signal Transduction; D013696:Temperature; D051176:beta Catenin / Q000378:metabolism
C473750:CBY1 protein, human; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C418741:TCIM protein, human; D051176:beta Catenin