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Copy of HPV-16 E2 protein

The interactions between the E2 protein and the DNA
by

Aleksandr Tseipek

on 8 July 2013

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Transcript of Copy of HPV-16 E2 protein

What is HPV-16?
E2 Protein:
What is its role?
7 Hydrogen bonds
Asn294, Lys297, Arg300, Arg302, Lys304, Thr316 located in alpha1 helix
His318 and Thr316 located in a beta2-beta 3 loop
5’ ACCg NNNN cGGT 3'
N(4) central spacer region

AT-rich spacer sequence increases affinity

300-fold difference in the affinity between tightest (AAAC) and weakest (GGCC) binding.

Electrostatic Interactions:
E2 General Structure
N-terminal transcription activation/replication domain
hinge region
C-terminal dimerization and DNA-binding domain
-beta barrel
-alpha helices (recognition)
Hydrogen bonding between E2 and DNA
HPV-16 DNA
E2-C Protein
STRUCTURAL AFFINITY
NON-COVALENT INTERACTIONS
REFERENCES
Major Groove Binding
HPV-Human Papillomavirus

HPV-16 strain is highly correlated with cervical carcinomas in humans

circular dsDNA virus enclosed in spherical capsid

E2-DNA Binding is Stabilized by Non-Covalent Interactions and DNA Bending
Prat-Gay, G. Gaston, K. and Cicero, D.O. (2008) The papillomavirus E2 DNA binding domain. Frontiers in Biosciences 13, 6006-6021.

Falconi, M. Oteri, F. Eliseo, T. Cicero, D.O., and Desideri, A. (2008) MD Simulations of Papillomavirus DNA-E2 Protein Complexes Hints at a Protein Structural Code for DNA Deformation. Biophysical Journal 95, 1108-1117.

Hegde, R.S. and Androphy, E.J. (1998) Crystal Structure of the E2 DNA-binding Human Papillomavirus Type 16: Implications for its DNA Binding-site Selection Mechanism. Journal of Molecular Biology 284, 1479-1489.

Hooley, E. Fairweather, V. Clarke, A.R. Gaston , K. and Brady R. L. (2006) The recognition of local DNA conformation by the human papillomavirus type 6 E2 protein. Nucleic Acids Research 34, 3897-3908.
recognition alpha helices bind to viral dsDNA via consecutive major grooves of consensus sequence

physical limitations
Major Groove
Consensus Sequence
Take Home Message!
E2 approaches prebent DNA binding sequence and alpha helices bind the consecutive major grooves
Binding is stabilized by electrostatic interactions between E2 and DNA backbone and hydrogen bonding between E2 and base pairs
AT Spacer & Prebending of DNA
Electrostatic
Hydrogen Bonding
regulates transcription & initiation of replication in vivo
Potential drug target-blocking E2 would block viral replication
Electrostatic Surface Potentials of DNA-binding domain
positive residues blue
BPV>HPV in positive charge
BPV positive charge strong enough to induce bending
HPV isn't positive enough
PYMOL Interactive Activity
E2 Protein Festive SONG
vs.
Favorable prebending of E2 DNA binding site towards the central minor groove

Intrinsic curving in the flanking major groove
Overall helix axis deflection of ~10 degrees
AT-rich allows for larger degrees of movement while GC-rich spacers are very rigid!
AT
spacer
GC
spacer
Nature of AT spacer DNA bending
E2 DNA Binding Consensus Sequence
E2 DNA Interactions
Zihan, Yu, Melissa
Full transcript