PXD060125

PXD060125 is an original dataset announced via ProteomeXchange.

Title	ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase as measured by hydrogen/deuterium exchange mass spectrometry (HDX-MS)
Description	Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, ANGPTL4, and ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation mediates the partitioning of lipid delivery to storage and metabolic tissues according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode-of-action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 stoichiometry between ANGPTL3 and ANGPTL8 and that ANGPTL3 is a homotrimer. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) studies revealed that both ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL’s α/β- hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from inactivation by unfolding, particularly against the unfolding triggered by ANGPTL3. Pulse-labelling HDX-MS studies revealed that ANGPTL3/8 and ANGPTL3 catalyze LPL unfolding in an ATP-independent fashion, which categorize these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3/8 explains why low plasma concentrations of ANGPTL3/8 are effective in inhibiting a molar excess of LPL in capillaries.
HostingRepository	PRIDE
AnnounceDate	2025-03-26
AnnouncementXML	Submission_2025-03-26_08:15:11.405.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Signe Bondesen
SpeciesList	scientific name: Bos taurus (Bovine); NCBI TaxID: 9913; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt G2 HDMS

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-23 12:55:21	ID requested
⏵ 1	2025-03-26 08:15:12	announced

Kumari A, Larsen SWR, Bondesen S, Qian Y, Tian HD, Walker SG, Davies BSJ, Remaley AT, Young SG, Konrad RJ, J, ø, rgensen TJD, Ploug M, ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase. Proc Natl Acad Sci U S A, 122(12):e2420721122(2025) [pubmed]

10.1073/pnas.2420721122;

submitter keyword: GPIHBP1, ANGPTL3/8,lipoprotein lipase, intravascular lipolysis, HDX-MS

Thomas J. D. Jørgensen
contact affiliation	Department of Biochemistry and Molecular Biology, Section for Biomedical Mass Spectrometry and Systems Biology, University of Southern Denmark
contact email	tjdj@bmb.sdu.dk
lab head
Signe Bondesen
contact affiliation	University of Southern Denmark
contact email	sibon20@student.sdu.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060125
     1. Label: PRIDE project
     2. Name: ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase as measured by hydrogen/deuterium exchange mass spectrometry (HDX-MS)