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PEDS Advance Access originally published online on February 13, 2009
Protein Engineering Design and Selection 2009 22(5):281-287; doi:10.1093/protein/gzp004
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

The C-terminal domain of the HIV-1 Vif protein is natively unfolded in its unbound state

Tali H. Reingewertz1, Hadar Benyamini1, Mario Lebendiker2, Deborah E. Shalev2 and Assaf Friedler1,3

1 Institute of Chemistry 2The Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, Safra Campus, Givat Ram, 91904 Jerusalem, Israel

3 To whom correspondence should be addressed. E-mail: assaf{at}chem.ch.huji.ac.il

The human immunodeficiency virus type-1 (HIV-1) Vif protein neutralizes the cellular defense mechanism against the virus. The C-terminal domain of Vif (CTD, residues 141–192) mediates many of its interactions. Full-length Vif is difficult to purify in large amounts, hence the only available structure of Vif is of residues 140–155 within the ElonginBC complex. Other structural information, derived from modeling and indirect experiments, indicates that the Vif CTD may be unstructured. Here, we chemically synthesized the Vif CTD using pseudo-proline-building blocks, studied its solution structure in the unbound state using biophysical techniques and found that it is unstructured under physiological conditions. The circular dichroism (CD) spectrum of Vif CTD showed a pattern of random coil with residual helical structure. The 15N-HSQC nuclear magnetic resonance (NMR) spectrum was characteristic of natively unfolded peptides. Vif CTD eluted from an analytical gel filtration column earlier than expected, indicating an extended conformation. Disorder predictions found the CTD to be unstructured, in agreement with our experimental results. CD experiments showed that Vif CTD underwent a conformational change upon interacting with membrane-mimicking DPC micelles, but not upon binding to a peptide derived from its binding region in ElonginC. Our results provide direct evidence for the unfolded structure of the free Vif CTD and indicate that it may gain structure upon binding its natural ligands.

Keywords: biophysics/HIV-1/natively unfolded proteins/peptides/Vif

Received January 7, 2009; revised January 7, 2009; accepted January 15, 2009.


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