Mapping the dynamic high-density lipoprotein synapse
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Date
2023-09
Publication Type
Journal Article
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yes
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Abstract
Background and aims: Heterogeneous high-density lipoprotein (HDL) particles, which can contain hundreds of proteins, affect human health and disease through dynamic molecular interactions with cell surface proteins. How HDL mediates its long-range signaling functions and interactions with various cell types is largely unknown. Due to the complexity of HDL, we hypothesize that multiple receptors engage with HDL particles resulting in condition-dependent receptor-HDL interaction clusters at the cell surface. Methods: Here we used the mass spectrometry-based and light-controlled proximity labeling strategy LUX-MS in a discovery-driven manner to decode HDL-receptor interactions. Results: Surfaceome nanoscale organization analysis of hepatocytes and endothelial cells using LUX-MS revealed that the previously known HDL-binding protein scavenger receptor B1 (SCRB1) is embedded in a cell surface protein community, which we term HDL synapse. Modulating the endothelial HDL synapse, composed of 60 proteins, by silencing individual members, showed that the HDL synapse can be assembled in the absence of SCRB1 and that the members are interlinked. The aminopeptidase N (AMPN) (also known as CD13) was identified as an HDL synapse member that directly influences HDL uptake into the primary human aortic endothelial cells (HAECs). Conclusions: Our data indicate that preformed cell surface residing protein complexes modulate HDL function and suggest new theragnostic opportunities.
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published
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Volume
380
Pages / Article No.
117200
Publisher
Elsevier
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Subject
High-density lipoprotein; HDL; Signaling; Interactome; Ligand-receptor interactions; Scavenger receptor B1; Surfaceome; Aminopeptidase; CD13; Spacial proteotyping; Chemoproteomics
Organisational unit
02072 - Proteomics Plattform D-HEST
Notes
Funding
ETH-30 17-1 - Light-mediated proximity detection of dynamic protein interactions (ETHZ)
160259 - Direct identification of lateral protein interactions in the plasma membrane of living cells and tissues (SNF)
160259 - Direct identification of lateral protein interactions in the plasma membrane of living cells and tissues (SNF)