Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1
Movement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis—low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactio...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227525000057 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823856927199723520 |
|---|---|
| author | Anamika Biswas Samina Arshid Kristian Kølby Kristensen Thomas J.D. Jørgensen Michael Ploug |
| author_facet | Anamika Biswas Samina Arshid Kristian Kølby Kristensen Thomas J.D. Jørgensen Michael Ploug |
| author_sort | Anamika Biswas |
| collection | DOAJ |
| description | Movement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis—low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactions with GPIHBP1’s intrinsically disordered N-terminal tail, which harbors two acidic clusters at positions 5–12 and 19–30. This polyanionic tail provides a molecular switch that controls LPL detachment from heparan sulfate proteoglycans (HSPGs) by competitive displacement. When the acidic tail was neutralized in gene-edited mice, LPL remained trapped in the sub-endothelial spaces triggering hypertriglyceridemia. Due to its disordered state, the crystal structure of LPL•GPIHBP1 provided no information on these electrostatic interactions between LPL and GPIHBP1 acidic tail. In the current study, we positioned the acidic tail on LPL using zero-length crosslinking. Acidic residues at positions 19–30 in GPIHBP1 mapped to Lys445, Lys441, Lys414, and Lys407 close to the interface between the C- and N-terminal domains in LPL. Modeling this interface revealed widespread polyelectrolyte interactions spanning both LPL domains, which explains why the acidic tail stabilizes LPL activity and protein conformation. In functional assays, we showed that the acidic cluster at 19–30 also had the greatest impact on preserving LPL activity, mitigating ANGPTL4-catalyzed LPL inactivation, preventing PSCK3-mediated LPL cleavage, and, importantly, displacing LPL from HSPGs. Our current study provides key insights into the biophysical mechanism(s) orchestrating intravascular compartmentalization of LPL activity—an intriguing pathway entailing competitive displacement of HSPG-bound LPL by a disordered acidic tail in GPIHBP1. |
| format | Article |
| id | doaj-art-b13e836a3dfa4115b557a89efe150525 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-b13e836a3dfa4115b557a89efe1505252025-02-12T05:29:21ZengElsevierJournal of Lipid Research0022-22752025-02-01662100745Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1Anamika Biswas0Samina Arshid1Kristian Kølby Kristensen2Thomas J.D. Jørgensen3Michael Ploug4Finsen Laboratory, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DenmarkFinsen Laboratory, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DenmarkFinsen Laboratory, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark; For correspondence: Michael PlougMovement of lipoprotein lipase (LPL) from myocytes or adipocytes to the capillary lumen is essential for intravascular lipolysis and plasma triglyceride homeostasis—low LPL activity in the capillary lumen causes hypertriglyceridemia. The trans-endothelial transport of LPL depends on ionic interactions with GPIHBP1’s intrinsically disordered N-terminal tail, which harbors two acidic clusters at positions 5–12 and 19–30. This polyanionic tail provides a molecular switch that controls LPL detachment from heparan sulfate proteoglycans (HSPGs) by competitive displacement. When the acidic tail was neutralized in gene-edited mice, LPL remained trapped in the sub-endothelial spaces triggering hypertriglyceridemia. Due to its disordered state, the crystal structure of LPL•GPIHBP1 provided no information on these electrostatic interactions between LPL and GPIHBP1 acidic tail. In the current study, we positioned the acidic tail on LPL using zero-length crosslinking. Acidic residues at positions 19–30 in GPIHBP1 mapped to Lys445, Lys441, Lys414, and Lys407 close to the interface between the C- and N-terminal domains in LPL. Modeling this interface revealed widespread polyelectrolyte interactions spanning both LPL domains, which explains why the acidic tail stabilizes LPL activity and protein conformation. In functional assays, we showed that the acidic cluster at 19–30 also had the greatest impact on preserving LPL activity, mitigating ANGPTL4-catalyzed LPL inactivation, preventing PSCK3-mediated LPL cleavage, and, importantly, displacing LPL from HSPGs. Our current study provides key insights into the biophysical mechanism(s) orchestrating intravascular compartmentalization of LPL activity—an intriguing pathway entailing competitive displacement of HSPG-bound LPL by a disordered acidic tail in GPIHBP1.http://www.sciencedirect.com/science/article/pii/S0022227525000057lipase/lipoproteintransportlipolysis and fatty acid metabolismtriglyceridesANGPTL4intrinsically disordered regions |
| spellingShingle | Anamika Biswas Samina Arshid Kristian Kølby Kristensen Thomas J.D. Jørgensen Michael Ploug Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1 Journal of Lipid Research lipase/lipoprotein transport lipolysis and fatty acid metabolism triglycerides ANGPTL4 intrinsically disordered regions |
| title | Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1 |
| title_full | Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1 |
| title_fullStr | Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1 |
| title_full_unstemmed | Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1 |
| title_short | Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1 |
| title_sort | competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in gpihbp1 |
| topic | lipase/lipoprotein transport lipolysis and fatty acid metabolism triglycerides ANGPTL4 intrinsically disordered regions |
| url | http://www.sciencedirect.com/science/article/pii/S0022227525000057 |
| work_keys_str_mv | AT anamikabiswas competitivedisplacementoflipoproteinlipasefromheparansulfateisorchestratedbyadisorderedacidicclusteringpihbp1 AT saminaarshid competitivedisplacementoflipoproteinlipasefromheparansulfateisorchestratedbyadisorderedacidicclusteringpihbp1 AT kristiankølbykristensen competitivedisplacementoflipoproteinlipasefromheparansulfateisorchestratedbyadisorderedacidicclusteringpihbp1 AT thomasjdjørgensen competitivedisplacementoflipoproteinlipasefromheparansulfateisorchestratedbyadisorderedacidicclusteringpihbp1 AT michaelploug competitivedisplacementoflipoproteinlipasefromheparansulfateisorchestratedbyadisorderedacidicclusteringpihbp1 |