Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets
Abstract Lipid droplets (LDs) are the main cellular storage sites for triacylglycerols (TAGs), playing an important role in energy homeostasis and cell signaling. Hydrolysis of the stored TAGs begins with conversion of TAGs into diacylglycerols (DAGs) by adipose triglyceride lipase (ATGL), followed...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58887-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849726736101539840 |
|---|---|
| author | Han Peng Qikui Xu Ting Zhang Jiakai Zhu Jinheng Pan Xiaoyu Guan Shan Feng Jianping Wu Qi Hu |
| author_facet | Han Peng Qikui Xu Ting Zhang Jiakai Zhu Jinheng Pan Xiaoyu Guan Shan Feng Jianping Wu Qi Hu |
| author_sort | Han Peng |
| collection | DOAJ |
| description | Abstract Lipid droplets (LDs) are the main cellular storage sites for triacylglycerols (TAGs), playing an important role in energy homeostasis and cell signaling. Hydrolysis of the stored TAGs begins with conversion of TAGs into diacylglycerols (DAGs) by adipose triglyceride lipase (ATGL), followed by hydrolysis of DAGs by hormone-sensitive lipase (HSL). Despite the central role of HSL in lipolysis, the molecular determinants for its LD association have remained elusive. Here, we report the cryo-EM structure of human HSL at 3.4 Å. Combining this with hydrogen-deuterium exchange mass spectrometry, biochemical and cellular assays, we identify residues 489-538, referred to as the “H-motif”, and the N-terminal 4-helix bundle of HSL as LD-binding motifs mediating direct interaction of HSL with LDs. LD binding mediated by the LD-binding motifs is independent of HSL phosphorylation catalyzed by the cAMP-dependent kinase PKA. Our findings provide insight into the LD binding mechanism of HSL, advancing our understanding of the regulation of lipolysis. |
| format | Article |
| id | doaj-art-15fb0cc8de1d4122a95ece92a0879a84 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-15fb0cc8de1d4122a95ece92a0879a842025-08-20T03:10:06ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-58887-zMolecular determinants for the association of human hormone-sensitive lipase with lipid dropletsHan Peng0Qikui Xu1Ting Zhang2Jiakai Zhu3Jinheng Pan4Xiaoyu Guan5Shan Feng6Jianping Wu7Qi Hu8College of Life Sciences, Zhejiang UniversityWestlake Laboratory of Life Sciences and BiomedicineSchool of Life Sciences, Westlake UniversitySchool of Life Sciences, Westlake UniversitySchool of Life Sciences, Westlake UniversitySchool of Life Sciences, Westlake UniversitySchool of Life Sciences, Westlake UniversityWestlake Laboratory of Life Sciences and BiomedicineSchool of Life Sciences, Westlake UniversityAbstract Lipid droplets (LDs) are the main cellular storage sites for triacylglycerols (TAGs), playing an important role in energy homeostasis and cell signaling. Hydrolysis of the stored TAGs begins with conversion of TAGs into diacylglycerols (DAGs) by adipose triglyceride lipase (ATGL), followed by hydrolysis of DAGs by hormone-sensitive lipase (HSL). Despite the central role of HSL in lipolysis, the molecular determinants for its LD association have remained elusive. Here, we report the cryo-EM structure of human HSL at 3.4 Å. Combining this with hydrogen-deuterium exchange mass spectrometry, biochemical and cellular assays, we identify residues 489-538, referred to as the “H-motif”, and the N-terminal 4-helix bundle of HSL as LD-binding motifs mediating direct interaction of HSL with LDs. LD binding mediated by the LD-binding motifs is independent of HSL phosphorylation catalyzed by the cAMP-dependent kinase PKA. Our findings provide insight into the LD binding mechanism of HSL, advancing our understanding of the regulation of lipolysis.https://doi.org/10.1038/s41467-025-58887-z |
| spellingShingle | Han Peng Qikui Xu Ting Zhang Jiakai Zhu Jinheng Pan Xiaoyu Guan Shan Feng Jianping Wu Qi Hu Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets Nature Communications |
| title | Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets |
| title_full | Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets |
| title_fullStr | Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets |
| title_full_unstemmed | Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets |
| title_short | Molecular determinants for the association of human hormone-sensitive lipase with lipid droplets |
| title_sort | molecular determinants for the association of human hormone sensitive lipase with lipid droplets |
| url | https://doi.org/10.1038/s41467-025-58887-z |
| work_keys_str_mv | AT hanpeng moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT qikuixu moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT tingzhang moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT jiakaizhu moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT jinhengpan moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT xiaoyuguan moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT shanfeng moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT jianpingwu moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets AT qihu moleculardeterminantsfortheassociationofhumanhormonesensitivelipasewithlipiddroplets |