PDBsum entry 2a01

Lipid transport

PDB id: 2a01

Contents

Protein chains

243 a.a. *

Ligands

AC9 ×7

Waters ×537

* Residue conservation analysis

Obsolete entry

PDB id:

2a01

Name:

Lipid transport

Title:

Crystal structure of lipid-free human apolipoprotein a-i

Structure:

Apolipoprotein a-i. Chain: a, b, c

Source:

Homo sapiens. Human. Organism_taxid: 9606. Other_details: blood plasma

Resolution:

2.40Å R-factor: 0.228 R-free: 0.249

Authors:

A.A.Ajees,G.M.Anantharamaiah,V.K.Mishra,M.M.Hussain,K.H.M.Murthy

Key ref:

A.A.Ajees et al. (2006). Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases. Proc Natl Acad Sci U S A, 103, 2126-2131. PubMed id: 16452169 DOI: 10.1073/pnas.0506877103

Date:

15-Jun-05 Release date: 21-Feb-06

Protein chains

P02647  (APOA1_HUMAN) -  Apolipoprotein A-I from Homo sapiens

Seq: 267 a.a.

Struc: 243 a.a.

DOI no: 10.1073/pnas.0506877103

Proc Natl Acad Sci U S A 103:2126-2131 (2006)

PubMed id: 16452169

Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases.

A.A.Ajees, G.M.Anantharamaiah, V.K.Mishra, M.M.Hussain, H.M.Murthy.

ABSTRACT

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.

Selected figure(s)

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.

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.

Figures were selected by the author.