Apolipoprotein A-I (Glu 198→Lys): A Mutant of the Major Apolipoprotein of High-Density Lipoproteins Occurring in a Family with Dyslipoproteinemia

Strobl, Wolfgang; Jabs, H.-U.; Hayde, Michael; Holzinger, T; Assmann, Gerd; Widhalm, Kurt

doi:10.1203/00006450-198808000-00017

Cited by 15 publications

(2 citation statements)

References 12 publications

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“…However, the presence of a Cys in the modified C-terminal domain of the protein may also explain the phenotype since this protein was found to form hetero-oligomers with apoA-II. A natural Glu 198¨L ys mutation has been described by Strobl et al (92) but it was not possible to firmly establish whether this mutation caused reduced HDL-C levels. In this case, half of the subjects carrying the mutation had normal HDL-C levels whereas the other half had HDL-C below the fifth percentile for age and sex.…”

Section: Apoa-i Mutagenesis and The Definition Of Lipid Binding Domainsmentioning

confidence: 99%

Apolipoprotein A-I: structure–function relationships

Frank

Marcel

2000

Journal of Lipid Research

266

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The inverse relationship between high density lipoprotein (HDL) plasma levels and coronary heart disease has been attributed to the role that HDL and its major constituent, apolipoprotein A-I (apoA-I), play in reverse cholesterol transport (RCT). The efficiency of RCT depends on the specific ability of apoA-I to promote cellular cholesterol efflux, bind lipids, activate lecithin:cholesterol acyltransferase (LCAT), and form mature HDL that interact with specific receptors and lipid transfer proteins. From the intensive analysis of apoA-I secondary structure has emerged our current understanding of its different classes of amphipathic ␣ -helices, which control lipid-binding specificity. The main challenge now is to define apoA-I tertiary structure in its lipid-free and lipid-bound forms. Two models are considered for discoidal lipoproteins formed by association of two apoA-I with phospholipids. In the first or picket fence model, each apoA-I wraps around the disc with antiparallel adjacent ␣ -helices and with little intermolecular interactions. In the second or belt model, two antiparallel apoA-I are paired by their C-terminal ␣ -helices, wrap around the lipoprotein, and are stabilized by multiple intermolecular interactions. While recent evidence supports the belt model, other models, including hybrid models, cannot be excluded. ApoA-I ␣ -helices control lipid binding and association with varying levels of lipids. The N-terminal helix 44-65 and the C-terminal helix 210-241 are recognized as important for the initial association with lipids. In the central domain, helix 100-121 and, to a lesser extent, helix 122-143, are also very important for lipid binding and the formation of mature HDL, whereas helices between residues 144 and 186 contribute little. The LCAT activation domain has now been clearly assigned to helix 144-165 with secondary contribution by helix 166-186. The lower lipid binding affinity of the region 144-186 may be important to the activation mechanism allowing displacement of these apoA-I helices by LCAT and presentation of the lipid substrates.No specific sequence has been found that affects diffusional efflux to lipid-bound apoA-I. In contrast, the C-terminal helices, known to be important for lipid binding and maintenance of HDL in circulation, are also involved in the interaction of lipid-free apoA-I with macrophages and specific lipid efflux. While much progress has been made, other aspects of apoA-I structure-function relationships still need to be studied, particularly its lipoprotein topology and its interaction with other enzymes, lipid transfer proteins and receptors important for HDL metabolism. -Frank, P. G., and Y. L. Marcel. Apolipoprotein A-I: structure-function relationships.

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Section: Apoa-i Mutagenesis and The Definition Of Lipid Binding Domainsmentioning

confidence: 99%

Apolipoprotein A-I: structure–function relationships

Frank

Marcel

2000

Journal of Lipid Research

266

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“…While most of them are linked with pathological phenotypes (e.g. deletion [6], non-conservative [7], nonsense [8], frameshift [9]), two variants, apoA-I Milano (apoA-IM) [10] and apoA-I Paris (apoA-IP) [11], appear to exhibit some unique, favourable features [10,12]. A common structural feature of the two variants is the presence of an arginine-to-cysteine mutation, at amino acid 173 in Milano and 151 in Paris.…”

Section: Introductionmentioning

confidence: 99%