HIV Viral
Infectivity Factor BC-box in complex with ElonginB and ElonginC
David Torres '16 and Joey Duronio '16
Contents:
I. Introduction
The
Human Immunodefiency Virus (HIV) as well as other similar
retroviruses contain a viral infectivity factor (Vif) that inhibits
certain anti-viral activity in human cells. Vif is used in viral
replication by hijacking the Cullin5 ECS ubiquitin ligase, which
consists of Cullin5, ElonginBC, andRbx2, and targeting APOBEC3G for
degradation. APOBEC3G is a cellular enzyme and part of the APOBEC
superfamily of proteins. This family of proteins plays a role in
anti-viral immunity. Vif inhibits APOBEC3G from entering the new
budding virus and hypermutating the genome to render the virus
essentially dead.
Vif
is able to hijack the ECS ubiquitin ligase by binding to ElonginBC
via the BC-box domain. It then uses the hosts own ubiquitination
and degradation system to destroy the APOBEC3G.
II.
General Structure of Vif and Elongin-Cullin-SOCS-box (ECS)
The
Vif BC-box
binds ElonginC
and ElonginB
similarly to how the human cellular SOCS box binds the ECS ubiquitin
ligase.A normal cellular ECS ubiquitin ligase
is made up ofElonginB(EloB)
, ElonginC(EloC),
Cullin5
(Cul5) , Rbx2, and a SOCS-box protein.
SOCS-box is formally known as the suppressor of cytokine signaling
box proteins. SOCS box proteins are characterized by a conserved
interaction domain, which offers a link between cellular substrates
and the E3 ubiquitin ligase. This conserved domain of SOCS box
includes the BC box, which binds EloB and EloC (EloBC), and the
Cullin box, which is hypothesized to participate in the binding of
either Cul5 or Cul2. Crystal structures show that the SOCS box has a
conserved region composed of a BC box helix, a small 90°
turn, a second short helix ending in a region rich with prolines, a
loop, and a third helix. The first helix is considered as the BC box
and the rest is referred to as the Cullin box.
The
structure of Vif
itself can be divided into two domains,
with a zinc ion binding between them. The larger domain (b
domain)binds one side of a protein called CBF-b. The
smaller domain of Vif (a
domain) interacts with EloC and Cul5. The carboxy-terminus
of CBF-b is sandwiched between the two domains of Vif. By
interacting with CBF-b, Cul5 and EloC, Vif organizes the formation
of the pentameric complex. This unique zinc-finger motif of Vif
located between the two domains makes no contacts with the other
proteins but stabilizes the conformation of the smaller domain,
which may be important in Vif-Cul5 binding.
III. Vif
Binding APOBEC3G and ElonginBC
Vif uses conserved regions
to influence the degradation of APOBEC3G. Vif acts as the substrate
of APOBEC3G by mimicking the SOCS box domain of a normal cellular
ECS ubiquitin ligase. Research proposes that the Vif N-terminal
domain interacts with APOBEC3G, while its C-terminal domain recruits
the ECS ligase through two conserved regions.
HIV Vif
contains a BC-box region that interacts with EloC and is crucial for
recruiting the cellular E3 ubiquitin ligase. A number of Vif
residues V142
, L145
, L148,L149,A152
, AND L153
create the hydrophobic face that interacts with EloC. Hydrogen
bonding between the backbone carbonyl of Vif
G143 and EloC
Y76
also contributes to the Vif-EloC interaction. A second ECS
ligase-binding domain is a conserved region containing histidine and
cysteine residues (this region is called the zinc-binding motif).
This zinc-binding motif interacts with Cul5. Mutations of these His
or Cys residues destroys the Vif-Cul5 interaction.
The interaction between a third Vif C-terminal domain, the
Vif Cullin box, and the ECS ubiquitin ligase has not been thoroughly
studied. However, the Vif-Cul5 interaction has been identified by
many experiments. These experiments were not able to identify a
direct interaction between the Vif Cullin box and Cul5.
IV. Future Studies
In
the past few years, much has been learned about how Vif recruits the
ECS ubiquitin ligase to destroy APOBEC3G. However, many of the
details still remain unclear due to the lack of structural data on
Vif itself (i.e. Vif not in complex with the EloBC box). Vif has yet
to be fully crystallized on its own which is why the zinc motif
residues and the terminal domains cannot be visualized here. Another
issue in studying how Vif interacts with ECS ubiquitin ligase is the
lack of structural data on the Cullin box. A possible future study
ito find out more details of the structure of these two molecules
would be to isolate Vif and the Cullin box and perform X-ray
crystallography on them to obtain the crystal three-dimensional
structure of Vif and the Cullin box. This crystal structure could
provide insight into more of the chemical interactions that occur
between Vif, ECS ubiquitin ligase, and the Cullin box. These studies
could also assist in the creation of a new anti-retroviral drug
therapy targeting Vif and allowing the human immune system to fight
HIV.
V. References
Stanley Bradford
J, Ehrlich Elana S, Short Leslie, Yu Yunkai, Xiao Zuoxiang, Yu
Fang-Xiao, Xiong Yong. Structural Insight into the Human
Immunodeficiency Virus Vif SOCS Box and Its Role in Human E3
Ubiquitin Ligase. Assembly
Department of Molecular Biophysics and Biochemistry, Yale
University, P.O. Box 208114, New Haven, Connecticut 06510,1 and
Department of Molecular Microbiology and Immunology, Bloomberg
School of Public Health, Johns Hopkins University, Baltimore,
Maryland 21205. 2010.
Bergeron JRC,
Huthoff H, Veselkov DA, Beavil RL, Simpson PJ, et al. (2010) The
SOCS-Box of HIV-1 Vif Interacts with ElonginBC by Induced-Folding to
Recruit Its Cul5-Containing Ubiquitin Ligase Complex. PLoS Pathog
6(6): e1000925. doi:10.1371/journal.ppat.1000925. 2010.
Marcisin Sean R,
Engen John R. Molecular Insight into the Conformational Dynamics of
the Elongin BC Complex and Its Interaction with HIV-1 Vif.
Department of Chemistry and
Chemical Biology and the Barnett Institute of Chemical and
Biological Analysis, Northeastern University, Boston, MA 02115,
USA. 2010.
Rose Kristine M,
Mariana Marin, Kozak Susan L, Kabat David. The viral infectivity
factor (Vif) of HIV-1 unveiled. Trends in Molecular Medicine. Vol 10, Issue 6. 2004.
Guo Yingying, Dong Liyong, Qiu Xiaolin,
Wang Yishu, Zhang Bailing, Liu Hongnan, Yu You, Zang Yi, Yang Maojun,
and Huang Zhiwei. Structural basis for hijacking CBF-β and CUL5 E3
ligase complex by HIV-1 Vif. Nature
505, 229–233. January 08 2014.
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