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Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis

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  5. A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

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  1. GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism

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  2. Evolution and Medical Significance of LU Domain-Containing Proteins

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  3. The PCNA interaction motifs revisited: thinking outside the PIP-box

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  4. Did evolution create a flexible ligand-binding cavity in the urokinase receptor through deletion of a plesiotypic disulfide bond?

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Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number5
Pages (from-to)1723-1732
ISSN0027-8424
DOIs
Publication statusPublished - 2019

ID: 56215211