A strained DNA binding helix is highly conserved for site recognition, folding nucleation and conformational modulation

WETZLER, D.E.; GALLO, M.; ELISEO, T.; NADRA, A.D.; FERREIRO, D.U.; SANCHEZ, I.E.; CICERO, D.O.; PRAT GAY, G. DE

BIOPOLYMERS

JOHN WILEY & SONS INC

Año: 2009 vol. 91 p. 432 - 443

0006-3525

Nucleic acid recognition is often mediated by a-helices ordisordered regions that fold into a-helix on binding. Apeptide bearing the DNA recognition helix of HPV16 E2displays type II polyproline (PII) structure as judged bypH, temperature, and solvent effects on the CD spectra.NMR experiments indicate that the canonical a-helix isstabilized at the N-terminus, while the PII forms at theC-terminus half of the peptide. Re-examination of thedihedral angles of the DNA binding helix in the crystalstructure and analysis of the NMR chemical shift indexesconfirm that the N-terminus half is a canonical a-helix,while the C-terminal half adopts a 310 helix structure.These regions precisely match two locally driven foldingnucleii, which partake in the native hydrophobic core andmodulate a conformational switch in the DNA bindinghelix. The peptide shows only weak and unspecificresidual DNA binding, 104-fold lower affinity, and 500-fold lower discrimination capacity compared with thedomain. Thus, the precise side chain conformationrequired for modulated and tight physiological binding byHPV E2 is largely determined by the noncanonicalstrained a-helix conformation, ‘‘presented’’ by thisunique architecture.