Ab initiomodelling of an essential mammalian protein: Transcription Termination Factor 1 (TTF1)

Abstract

Transcription Termination Factor 1 (TTF1) is an essential mammalian protein that regulates cellular transcription, replication fork arrest, DNA damage repair, chromatin remodelling etc. TTF1 interacts with numerous cellular proteins to regulate various cellular phenomena, and plays a crucial role in maintaining normal cellular physiology, dysregulation of which has been reported towards cancerous transformation of the cells. However, despite its key role in cellular physiology, the complete structure of human TTF1 has not been elucidated to date, either experimentally or computationally. Hence, understanding the structure of human TTF1 becomes highly important for studying its functions and interactions with other cellular factors. Therefore, the aim of this study was to construct the complete structure of human TTF1 protein, using molecular modelling approaches. Owing to the lack of suitable homologues in the PDB, the complete structure of human TTF1 was constructed using ab initio modelling. The structural stability was determined using molecular dynamics (MD) simulations in explicit solvent, and trajectory analyses. The representative structure of human TTF1 was obtained by trajectory clustering, and the central residues were determined by centrality analyses of the residue interaction network of TTF1. Two residue clusters, in the oligomerisation domain and C-terminal domain, were determined to be central to the structural stability of human TTF1. To the best of our knowledge, this study is the first to report the complete structure of human TTF1, and the results obtained herein will provide structural insights for future research in cancer biology and related studies.

Purification and Structural Characterization of N-Terminal 190 Amino Acid Deleted Essential Mammalian Protein; Transcription Termination Factor 1

“…Deconvolution of spectra collected from CD and Raman spectroscopy shows that TTF1 is a helical protein, and this finding justifies its DNA-binding activity. The above finding is in agreement with our computational model for the full-length TTF1 as well . Previous publications reporting protein DNA atomic structures have shown that the DNA is stabilized between the helices of those proteins. , …”

“…The secondary structure estimation after spectral deconvolution (as mentioned in the Materials and Methods section) gave estimated percentages of α helices (53.46%), β sheets (9.7%), random coils (23.78%), and turns (12.88%) (average of five runs, Table ), confirming the predominantly helical nature of the protein . The above finding is very much in agreement with our computational ab initio study and simulation data on human TTF1 protein …”

“…Even though TTF1 is an essential multifunctional protein, almost nothing is known about its biophysical character or structure. The only study revealing its structural model (computationally) is reported from our lab . Hence, it is important to understand the biophysical characters of this protein in order to engineer the same for structural and mechanistic studies.…”

“…However, to date, no research on its structural, computational, or physical characterization has been reported yet. The very first article that reports ab initio modeling of this essential protein has been communicated from our lab . Considering the multifunctional and essential nature of TTF1, it becomes important to elucidate the structural knowledge in order to understand its mechanisms of action and use the same toward its therapeutic applications.…”

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of EGFR mutations in lung adenocarcinoma patients

“…In this study, females had higher EGFR mutation rates than males, and never smokers had more EGFR mutations than ever smokers, which aligns with previous studies (15,22). Second, previous data had demonstrated, the positive expression of TTF-1 has a significant positive correlation with EGFR mutations in patients with LUADs, and if the expression of TTF-1 was negative, there was a 95% chance of wild-type EGFR mutation (17)(18)(19). In the current study, among 362 patients, there were 329 cases (92.3%) with the positive expression of TTF-1.…”