Identification of Structural Mutations in the Fifth Domain of Apolipoprotein H (β2-Glycoprotein I) Which Affect Phospholipid Binding

Apolipoprotein H (apoH), also known as β2-glycoprotein-I, is considered to be a cofactor for the binding of certain antiphospholipid autoantibodies to negatively charged phospholipids. Genetically determined structural abnormalities in the lipid binding domain(s) of apoH can affect its ability to bi...

Full description

Saved in:
Bibliographic Details
Published in:Human molecular genetics 1997-02, Vol.6 (2), p.311-316
Main Authors: Sanghera, Dharambir K., Wagenknecht, Dawn R., McIntyre, John A., Kamboh, M. Ilyas
Format: Article
Language:English
Subjects:
Alleles
Allergic diseases
Amino Acid Sequence
beta 2-Glycoprotein I
Binding Sites
Biological and medical sciences
Codon
Glycoproteins - genetics
Glycoproteins - metabolism
Humans
Immunopathology
Medical sciences
Molecular Sequence Data
Mutation
Other localizations
Phospholipids - chemistry
Phospholipids - metabolism
Protein Binding
Protein Conformation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Apolipoprotein H (apoH), also known as β2-glycoprotein-I, is considered to be a cofactor for the binding of certain antiphospholipid autoantibodies to negatively charged phospholipids. Genetically determined structural abnormalities in the lipid binding domain(s) of apoH can affect its ability to bind lipid and consequently the production of the autoantibodies. In this study we have identified two common structural mutations at codons 316 and 306 in the fifth domain of apoH which rendered apoH unable to bind to negatively charged phosphatidylserine (PS). The missense mutation at codon 316 (TGG→TCG) replaces Trp316 with Ser316 and disrupts the integrity of four highly conserved hydrophobic amino acids sequence at positions 313–316, which is a potential protein-lipid hydrophobic interaction site. The missense mutation at codon 306 (TGC→GGC) involves the substitution of Cys306 by Gly306 which causes the disruption of a disulfide bond between Cys281 and Cys306 and affects the normal configuration of the fifth domain of apoH that appears to be critical for clustering positively charged amino acids along with the four hydrophobic amino acids sequence. ApoH from the two homozygotes (Ser316/Ser316) and all seven compound heterozygotes (Ser316/Gly306) failed to bind to PS; all heterozygotes at one or the other sites and wild type showed normal PS binding. These data indicate that the fifth domain of apoH harbors the lipid binding region. An estimated 2 million Caucasians in the United States, who are compound heterozygotes for the two mutations, may be precluded from producing apoH-dependent antiphospholipid autoantibodies.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/6.2.311