Related Experiment Videos
Molecular belt models for the apolipoprotein A-I Paris and Milano mutations
A E Klon1, M K Jones, J P Segrest
1Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294 USA.
Abstract:
Models for the binding of the 200-residue carboxy-terminal domain of two mutants of apolipoprotein A-I (apo A-I), apo A-I(R173C)(Milano) and apo A-I(R151C)(Paris), to lipid in discoidal high-density lipoprotein (HDL) particles are presented. In both models, two monomers of the mutant apo A-I molecule bind to lipid in an antiparallel manner, with the long axes of their helical repeats running perpendicular to the normal of the lipid bilayer to form a single disulfide-linked homodimer. The overall structures of the models of these two mutants are very similar, differing only in helix-helix registration. Thus these models are consistent with experimental observations that reconstituted HDL particles containing apo A-I(Milano) and apo A-I(Paris) are very similar in diameter to reconstituted HDL particles containing wild-type apo A-I, and they support the belief that apo A-I binds to lipid in discoidal HDL particles via the belt conformation.
Insights
Models reveal how two mutant apolipoprotein A-I (apo A-I) forms bind lipids in high-density lipoprotein (HDL) particles. These structures suggest apo A-I utilizes a belt conformation for lipid binding in discoidal HDL.
Area of Science:
- Biochemistry
- Structural Biology
- Lipid Metabolism
Background:
- Apolipoprotein A-I (apo A-I) is the primary protein component of high-density lipoprotein (HDL).
- Mutations in apo A-I, such as apo A-I(Milano) and apo A-I(Paris), can affect HDL structure and function.
- Understanding apo A-I's interaction with lipids is crucial for comprehending HDL assembly and reverse cholesterol transport.
Purpose of the Study:
- To develop structural models for the binding of two apo A-I mutants, apo A-I(R173C)(Milano) and apo A-I(R151C)(Paris), to discoidal HDL particles.
- To elucidate the mechanism of apo A-I interaction with lipid bilayers in the context of HDL.
Main Methods:
- Development of molecular models based on the carboxy-terminal domain of apo A-I mutants.
- Analysis of monomer-monomer interactions and orientation relative to the lipid bilayer.
- Comparison of model structures with experimental data on reconstituted HDL particles.
Main Results:
- Models show two mutant apo A-I monomers binding lipids in an antiparallel orientation.
- A single disulfide-linked homodimer is formed, with helical repeats perpendicular to the lipid bilayer.
- The overall structures of apo A-I(Milano) and apo A-I(Paris) models are highly similar, differing in helix registration.
Conclusions:
- The proposed models are consistent with experimental observations of reconstituted HDL particle sizes.
- These findings support the 'belt' conformation model for apo A-I binding to lipids in discoidal HDL.
- Structural insights into apo A-I mutants provide a basis for understanding their functional consequences.