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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
37
4-POS
Board 4
Conformational Ensembles of the HIV Vif Complex
K. Aurelia Ball
1
, Lieza Chan
1
, Eliese Tierney
1
, David Stanley
3
, Matthew Jacobson
2
, John
Gross
2
.
1
Skidmore College, Saratoga Springs, NY, USA,
2
University of California San Francisco, San
Francisco, CA, USA,
3
University Of California Berkeley, Berkeley, CA, USA.
Like many viruses, HIV hijacks the host cell's apparatus for normal protein ubiquitination and
degradation, using it to eliminate antiviral proteins. Understanding how a virus recruits and
targets the ubqiuitination complex is critical for developing therapeutics to prevent it. One HIV
protein responsible for this hijacking is Virion infectivity factor (Vif). Vif is intrinsically
disordered but loses flexibility as it binds more host proteins, a process that may be crucial for
function. We are investigating the complex formed with Vif and the host proteins Elongin B
(EloB), Elongin C (EloC), and Core-Binding Factor subunit beta (CBF-beta) to determine what
remaining conformational flexibility Vif retains as part of this large complex with folded
proteins. Using molecular dynamics simulations, we have found that this Vif-host protein
complex exhibits large-scale conformational changes and occupies alternate conformational
states. These conformational dynamics are altered when additional proteins such as Cullin 5, part
of the ubiquitination complex, or APOBEC3F, an antiviral protein targeted by Vif for
ubiquitination, are bound to the complex. We observe a reduction in large scale motions of the
complex and a reduction in the sampling of the conformational landscape when an additional
protein is bound. Additionally, we find that the partially disordered C-terminus of EloB is
important for the structural stability of the complex. These computational results are supported
by methyl-labeled NMR spectroscopy. The alternate conformations sampled in our simulations
are important for better understanding the function of the complex in ubiquitinating APOBEC, as
well as how a disordered protein like Vif can affect the dynamics of a larger complex of folded
proteins.