1tjj

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Human GM2 Activator Protein PAF complex

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

GM2-activator protein (GM2-AP) is a lipid transfer protein that has the, ability to stimulate the enzymatic processing of gangliosides as well as, T-cell activation through lipid presentation. Our previous X-ray, crystallographic studies of GM2-AP have revealed a large lipid binding, pocket as the central overall feature of the structure with non-protein, electron density within this pocket suggesting bound lipid. To extend, these studies, we present here the 2A crystal structure of GM2-AP, complexed with platelet activating factor (PAF). PAF is a potent, phosphoacylglycerol whose toxic patho-physiological effects can be, inhibited by GM2-AP. The structure shows an ordered arrangement of two, bound lipids and a fatty acid molecule. One PAF molecule binds in an, extended conformation within the hydrophobic channel that has an open and, closed conformation, and was seen to contain bound phospholipid in the low, pH apo structure. The second molecule is submerged inside the pocket in a, U-shaped conformation with its head group near the single polar residue, S141. It was refined as lyso-PAF as it lacks electron density for the sn-2, acetate group. The alkyl chains of PAF interact through van der Waals', contacts, while the head groups bind in different environments with their, phosphocholine moieties in contact with aromatic rings (Y137, F80). The, structure has revealed further insights into the lipid binding properties, of GM2-AP, suggesting an unexpected unique mode of lipid packaging that, may explain the efficiency of GM2-AP in inhibiting the detrimental, biological effects of PAF.

Disease

Known disease associated with this structure: GM2-gangliosidosis, AB variant OMIM:[272750]

About this Structure

1TJJ is a Single protein structure of sequence from Homo sapiens with ACT, CL, EPE, PFS, LPE, DAO and IPA as ligands. Full crystallographic information is available from OCA.

Reference

Evidence for lipid packaging in the crystal structure of the GM2-activator complex with platelet activating factor., Wright CS, Mi LZ, Rastinejad F, J Mol Biol. 2004 Sep 10;342(2):585-92. PMID:15327957

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