Strain 16 of the human papillomavirus is responsible for the largest number of cases of cervical cancers linked to this virus, and the E2 protein is the transcriptional regulator of all viral genes. We present the first structure for the DNA binding domain of HPV16 E2 bound to DNA, and in particular, to a natural cognate sequence. The NMR structure of the protein backbone reveals that the overall conformation remains virtually unchanged, and chemical shift analysis of the protein bound to a shorter DNA duplex uncovered a contact out of the minimal E2 DNA binding site, made by lysine 349. This contact was confirmed by titration calorimetry and mutagenesis, with a contribution of 1.0 kcal mol(-1) to binding energy. HPV16 E2 has the highest DNA binding affinity and exerts a strict transcriptional control, translated into the repression of the E6 and E7 oncogenes. These novel features provide the structural and thermodynamic basis for this tight transcriptional control, the loss of which correlates with carcinogenesis.

Cicero, D.o., Nadra, A., Eliseo, T., Dellarole, M., Paci, M., De Prat Gay, G. (2006). Structural and thermodynamic basis for the enhanced transcriptional control by the human papillomavirus strain-16 E2 protein. BIOCHEMISTRY, 45(21), 6551-6560 [10.1021/bi060123h].

Structural and thermodynamic basis for the enhanced transcriptional control by the human papillomavirus strain-16 E2 protein

CICERO, DANIEL OSCAR;PACI, MAURIZIO;
2006-01-01

Abstract

Strain 16 of the human papillomavirus is responsible for the largest number of cases of cervical cancers linked to this virus, and the E2 protein is the transcriptional regulator of all viral genes. We present the first structure for the DNA binding domain of HPV16 E2 bound to DNA, and in particular, to a natural cognate sequence. The NMR structure of the protein backbone reveals that the overall conformation remains virtually unchanged, and chemical shift analysis of the protein bound to a shorter DNA duplex uncovered a contact out of the minimal E2 DNA binding site, made by lysine 349. This contact was confirmed by titration calorimetry and mutagenesis, with a contribution of 1.0 kcal mol(-1) to binding energy. HPV16 E2 has the highest DNA binding affinity and exerts a strict transcriptional control, translated into the repression of the E6 and E7 oncogenes. These novel features provide the structural and thermodynamic basis for this tight transcriptional control, the loss of which correlates with carcinogenesis.
2006
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10 - BIOCHIMICA
English
Con Impact Factor ISI
Binding energy; Calorimetry; Carcinogens; DNA; Mutagenesis; Thermodynamics; Tumors; Viruses; Binding affinity; Carcinogenesis; DNA duplex; Transcriptional control; Proteins; carbon 13; nitrogen 15; virus DNA; virus protein; article; binding affinity; binding site; carbon nuclear magnetic resonance; DNA binding; DNA protein complex; DNA virus; enthalpy; genetic transcription; Human papillomavirus type 16; isotope labeling; nitrogen nuclear magnetic resonance; nonhuman; priority journal; proton nuclear magnetic resonance; thermodynamics; transcription regulation; virus typing; Wart virus; Amino Acid Sequence; Base Sequence; DNA-Binding Proteins; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Oligonucleotides; Oncogene Proteins, Viral; Protein Conformation; Sequence Homology, Amino Acid; Thermodynamics; Transcription, Genetic; Human papillomavirus
Cicero, D.o., Nadra, A., Eliseo, T., Dellarole, M., Paci, M., De Prat Gay, G. (2006). Structural and thermodynamic basis for the enhanced transcriptional control by the human papillomavirus strain-16 E2 protein. BIOCHEMISTRY, 45(21), 6551-6560 [10.1021/bi060123h].
Cicero, Do; Nadra, A; Eliseo, T; Dellarole, M; Paci, M; De Prat Gay, G
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/34561
Citazioni
  • ???jsp.display-item.citation.pmc??? 12
  • Scopus ND
  • ???jsp.display-item.citation.isi??? 24
social impact