INVESTIGADORES
ALONSO Leonardo Gabriel
artículos
Título:
The N-Terminal Module of HPV16 E7 Is an Intrinsically Disordered Domain That Confers Conformational and Recognition Plasticity to the Oncoprotein
Autor/es:
MARIA M. GARCÍA-ALAI; LEONARDO G. ALONSO; GONZALO DE PRAT-GAY
Revista:
BIOCHEMISTRY
Editorial:
AMER CHEMICAL SOC
Referencias:
Año: 2007 vol. 46 p. 10405 - 10412
ISSN:
0006-2960
Resumen:
The HPV16 E7 oncoprotein is an extended dimer, with a stable and
cooperative fold, but that displays properties of natively unfolded
proteins. Two regions of conserved sequence are found in E7 proteins,
where the N-terminus (1−40) includes the retinoblastoma tumor suppressor
binding and casein kinase II phosphorylation sites. A fragment
containing the highly acidic N-terminal half shows an apparently
disordered conformation by far-UV−circular dichroism (CD) at neutral pH,
and its hydrodynamic radius is much larger than a neutral peptide of
the same length. Trifluoroethanol and micellar concentrations of sodium
dodecyl sulfate stabilize a much more helical structure at pH 4.0 than
at pH 7.5, while submicellar concentrations of the detergent yield a
β-strand. The shape, pH, and temperature dependence of the CD spectrum
at pH 7.5 are indicative of a poly proline type II structure. This
structure is stabilized by phosphorylation, which would translate into
increased transforming activity in the cell. Thus, the intrinsically
disordered properties of the N-terminal module of E7 are responsible for
the structural plasticity of the oncoprotein. Although the domain is
not a compact and cooperatively folded unit, it is a bona fide
functional domain, evolved to maintain a dynamic but extended structure
in the cell. These properties allow adaptation to a variety of protein
targets and expose the PEST degradation sequence that regulates its
turnover in the cell, a modification of which leads to the accumulation
of E7 species with consequences in the transformation process