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Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 8, Kristensen, K K, Leth-Espensen, K Z, Mertens, H D T, Birrane, G, Meiyappan, M, Olivecrona, G, Jørgensen, T J D, Young, S G & Ploug, M 2020, ' Unfolding of monomeric lipoprotein lipase by ANGPTL4 : Insight into the regulation of plasma triglyceride metabolism ', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 8, pp. 4337-4346 . https://doi.org/10.1073/pnas.1920202117, Proc Natl Acad Sci U S A
- Publication Year :
- 2020
- Publisher :
- eScholarship, University of California, 2020.
-
Abstract
- The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.
- Subjects :
- 0301 basic medicine
Amino Acid Motifs
Adipose tissue
lipoprotein lipase
030204 cardiovascular system & hematology
Antibodies
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
ANGPTL4
Receptors
Monoclonal
medicine
Animals
Humans
Angiopoietin-Like Protein 4
HDX-MS
Lipoprotein
Triglycerides
Receptors, Lipoprotein
Protein Unfolding
chemistry.chemical_classification
Hypertriglyceridemia
Lipoprotein lipase
Multidisciplinary
Triglyceride
Chemistry
GPIHBP1
digestive, oral, and skin physiology
Antibodies, Monoclonal
Skeletal muscle
nutritional and metabolic diseases
Metabolism
Biological Sciences
intravascular lipolysis
Lipoprotein Lipase
030104 developmental biology
medicine.anatomical_structure
Enzyme
Biochemistry
lipids (amino acids, peptides, and proteins)
Dimerization
surface plasmon resonance
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, vol 117, iss 8, Kristensen, K K, Leth-Espensen, K Z, Mertens, H D T, Birrane, G, Meiyappan, M, Olivecrona, G, Jørgensen, T J D, Young, S G & Ploug, M 2020, ' Unfolding of monomeric lipoprotein lipase by ANGPTL4 : Insight into the regulation of plasma triglyceride metabolism ', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 8, pp. 4337-4346 . https://doi.org/10.1073/pnas.1920202117, Proc Natl Acad Sci U S A
- Accession number :
- edsair.doi.dedup.....21fbd7c42fd5e10747c61f1a1d096520