Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome
Abstract Biogenesis of lysosome-related organelle complex-3 (BLOC-3) is pivotal in vesicle trafficking and has been linked to Hermansky-Pudlak syndrome (HPS). Despite its importance, the structure and molecular function of BLOC-3 remains elusive. Here, we report the Cryo-EM structure of human BLOC-3...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58235-1 |
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| author | Xin Yong Guowen Jia Qin Yang Chunzhuang Zhou Sitao Zhang Huaqing Deng Daniel D. Billadeau Zhaoming Su Da Jia |
| author_facet | Xin Yong Guowen Jia Qin Yang Chunzhuang Zhou Sitao Zhang Huaqing Deng Daniel D. Billadeau Zhaoming Su Da Jia |
| author_sort | Xin Yong |
| collection | DOAJ |
| description | Abstract Biogenesis of lysosome-related organelle complex-3 (BLOC-3) is pivotal in vesicle trafficking and has been linked to Hermansky-Pudlak syndrome (HPS). Despite its importance, the structure and molecular function of BLOC-3 remains elusive. Here, we report the Cryo-EM structure of human BLOC-3 at 3.2 Å resolution. The BLOC-3 complex consists of one copy of HPS1 and HPS4, which tightly associate with each other via their longin domains (LD1 and LD3). The unique four-helical bundle (4HB) domain of HPS1 is involved in stabilizing its LD1 and LD2 domains. Moreover, we identify interactions between BLOC-3 and the small GTPases RAB32/38 and RAB9A, which are essential for lysosome-related organelle biogenesis. Functional assays using zebrafish models confirm the significance of BLOC-3 assembly and its interaction with RAB9A during melanosome biogenesis. Most importantly, our structural information provides an accurate prediction for clinical variants associated with HPS. In summary, our study provides a comprehensive understanding of the molecular architecture and functional roles of BLOC-3, shedding light on HPS pathogenesis. |
| format | Article |
| id | doaj-art-f38cb813ace44fbb97d8cc33fed1d42e |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-f38cb813ace44fbb97d8cc33fed1d42e2025-08-20T02:10:10ZengNature PortfolioNature Communications2041-17232025-03-0116111510.1038/s41467-025-58235-1Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndromeXin Yong0Guowen Jia1Qin Yang2Chunzhuang Zhou3Sitao Zhang4Huaqing Deng5Daniel D. Billadeau6Zhaoming Su7Da Jia8Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan UniversityState Key Laboratory of Biotherapy, Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityKey Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan UniversityKey Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan UniversityKey Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan UniversityKey Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan UniversityDivision of Oncology Research and Schulze Center for Novel Therapeutics, Mayo ClinicState Key Laboratory of Biotherapy, Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityKey Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan UniversityAbstract Biogenesis of lysosome-related organelle complex-3 (BLOC-3) is pivotal in vesicle trafficking and has been linked to Hermansky-Pudlak syndrome (HPS). Despite its importance, the structure and molecular function of BLOC-3 remains elusive. Here, we report the Cryo-EM structure of human BLOC-3 at 3.2 Å resolution. The BLOC-3 complex consists of one copy of HPS1 and HPS4, which tightly associate with each other via their longin domains (LD1 and LD3). The unique four-helical bundle (4HB) domain of HPS1 is involved in stabilizing its LD1 and LD2 domains. Moreover, we identify interactions between BLOC-3 and the small GTPases RAB32/38 and RAB9A, which are essential for lysosome-related organelle biogenesis. Functional assays using zebrafish models confirm the significance of BLOC-3 assembly and its interaction with RAB9A during melanosome biogenesis. Most importantly, our structural information provides an accurate prediction for clinical variants associated with HPS. In summary, our study provides a comprehensive understanding of the molecular architecture and functional roles of BLOC-3, shedding light on HPS pathogenesis.https://doi.org/10.1038/s41467-025-58235-1 |
| spellingShingle | Xin Yong Guowen Jia Qin Yang Chunzhuang Zhou Sitao Zhang Huaqing Deng Daniel D. Billadeau Zhaoming Su Da Jia Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome Nature Communications |
| title | Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome |
| title_full | Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome |
| title_fullStr | Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome |
| title_full_unstemmed | Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome |
| title_short | Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome |
| title_sort | cryo em structure of the bloc 3 complex provides insights into the pathogenesis of hermansky pudlak syndrome |
| url | https://doi.org/10.1038/s41467-025-58235-1 |
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