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PDBsum entry 2a01
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Lipid transport
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PDB id
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2a01
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References listed in PDB file
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Key reference
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Title
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Crystal structure of human apolipoprotein a-I: insights into its protective effect against cardiovascular diseases.
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Authors
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A.A.Ajees,
G.M.Anantharamaiah,
V.K.Mishra,
M.M.Hussain,
H.M.Murthy.
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Ref.
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Proc Natl Acad Sci U S A, 2006,
103,
2126-2131.
[DOI no: ]
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PubMed id
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Abstract
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Despite three decades of extensive studies on human apolipoprotein A-I (apoA-I),
the major protein component in high-density lipoproteins, the molecular basis
for its antiatherogenic function is elusive, in part because of lack of a
structure of the full-length protein. We describe here the crystal structure of
lipid-free apoA-I at 2.4 A. The structure shows that apoA-I is comprised of an
N-terminal four-helix bundle and two C-terminal helices. The N-terminal domain
plays a prominent role in maintaining its lipid-free conformation, indicating
that mutants with truncations in this region form inadequate models for
explaining functional properties of apoA-I. A model for transformation of the
lipid-free conformation to the high-density lipoprotein-bound form follows from
an analysis of solvent-accessible hydrophobic patches on the surface of the
structure and their proximity to the hydrophobic core of the four-helix bundle.
The crystal structure of human apoA-I displays a hitherto-unobserved array of
positively and negatively charged areas on the surface. Positioning of the
charged surface patches relative to hydrophobic regions near the C terminus of
the protein offers insights into its interaction with cell-surface components of
the reverse cholesterol transport pathway and antiatherogenic properties of this
protein. This structure provides a much-needed structural template for
exploration of molecular mechanisms by which human apoA-I ameliorates
atherosclerosis and inflammatory diseases.
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Figure 1.
Fig. 1. Overall stereoview of the structure. The six
helices in the structure are rendered as C^  worms, colored blue
(A), pink (B), yellow (C), lavender (D), cyan (E), and red (F)
and labeled. Loops are colored gold. Hydrophobic residues are
shown as green sticks.
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Figure 3.
Fig. 3. Model for lipid-assisted conversion. Helices are
represented as cylinders and colored as in Fig. 1. Hydrophobic
residues are depicted as green sticks. The C-terminal domain is
shown as a C^ worm in an arbitrary
orientation and position as a single, long helix. (A) Initial
lipid-free conformation of apoA-I. Residues contributing to the
hydrophobic patch at the N terminus of helix 1 are shown. (B and
C) The two geometrically possible open conformations, formed
through lipid binding to the bundle. The energetically more
likely conformation (C) is indicated by a solid arrow.
Hydrophobic side chains that contribute to the four-helix bundle
interface are exposed. (D) Rearrangement of a fraction of the
open form into a stable helix-hairpin intermediate. Residues
forming the new hydrophobic stabilization core are illustrated.
(E) Putative conformation in the HDL-bound form, represented by
the  1-43 structure.
Hydrophobic residues that could potentially form the interaction
interface with lipid in HDL are shown.
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