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PDBsum entry 2k4h
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Structural protein
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PDB id
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2k4h
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References listed in PDB file
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Key reference
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Title
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Structure of the myristylated human immunodeficiency virus type 2 matrix protein and the role of phosphatidylinositol-(4,5)-Bisphosphate in membrane targeting.
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Authors
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J.S.Saad,
S.D.Ablan,
R.H.Ghanam,
A.Kim,
K.Andrews,
K.Nagashima,
F.Soheilian,
E.O.Freed,
M.F.Summers.
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Ref.
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J Mol Biol, 2008,
382,
434-447.
[DOI no: ]
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PubMed id
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Abstract
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During the late phase of retroviral replication, newly synthesized Gag proteins
are targeted to the plasma membrane (PM), where they assemble and bud to form
immature virus particles. Membrane targeting by human immunodeficiency virus
type 1 (HIV-1) Gag is mediated by the PM marker molecule
phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)], which is capable of
binding to the matrix (MA) domain of Gag in an extended lipid conformation and
of triggering myristate exposure. Here, we show that, as observed previously for
HIV-1 MA, the myristyl group of HIV-2 MA is partially sequestered within a
narrow hydrophobic tunnel formed by side chains of helices 1, 2, 3, and 5.
However, the myristate of HIV-2 MA is more tightly sequestered than that of the
HIV-1 protein and does not exhibit concentration-dependent exposure. Soluble
PI(4,5)P(2) analogs containing truncated acyl chains bind HIV-2 MA and induce
minor long-range structural changes but do not trigger myristate exposure.
Despite these differences, the site of HIV-2 assembly in vivo can be manipulated
by enzymes that regulate PI(4,5)P(2) localization. Our findings indicate that
HIV-1 and HIV-2 are both targeted to the PM for assembly via a
PI(4,5)P(2)-dependent mechanism, despite differences in the sensitivity of the
MA myristyl switch, and suggest a potential mechanism that may contribute to the
poor replication kinetics of HIV-2.
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Figure 4.
Fig. 4. A representative structure of HIV-2 myr(+)MA (slate)
and comparison with the HIV-1 myr(+)MA protein (sand). (a)
Semitransparent surface representation of MA showing the
penetration of the myr group (red sticks) and interactions with
the side chains of Val7, Leu8, Leu16, Ile34, and ILe85 (green
sticks). (b) Cartoon representation of the HIV-2 and HIV-1
myr(+)MA proteins comparing the sequestration of the myristate
group (red) in the hydrophobic cavity formed by residues Val7,
Leu8, Leu16, Ile34, and Ile85 (green spheres). (c)
Superimposition of representative structures of HIV-2 and HIV-1
myr(+)MA. Myristate groups of HIV-2 and HIV-1 myr(+)MA proteins
are packing against Leu16 and Trp16, respectively. NMR data
revealed that helix 6 is flexible for both proteins. (d) An
expanded view of the protein core of HIV-2 and HIV-1 myr(+)MA
showing the myristate packing against side chains of Leu16 and
Trp16, respectively.
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Figure 7.
Fig. 7. Structure of the HIV-2 myr(+)MA/di-C[4]-PI(4,5)P[2]
complex. (a,b) Interactions between di-C[4]-PI(4,5)P[2] (sticks)
and MA (colored according to electrostatic surface potential)
showing the 2′-fatty acid inserting in a preexisting cleft and
the inositol ring packing against a basic patch of the protein.
(c) PI(4,5)P[2] binding to the β-II–V cleft. (d) A network of
interactions implicated in PI(4,5)P[2] binding.
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The above figures are
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2008,
382,
434-447)
copyright 2008.
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