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Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome

Author

Listed:
  • Xin Yong

    (Sichuan University)

  • Guowen Jia

    (Sichuan University)

  • Qin Yang

    (Sichuan University)

  • Chunzhuang Zhou

    (Sichuan University)

  • Sitao Zhang

    (Sichuan University)

  • Huaqing Deng

    (Sichuan University)

  • Daniel D. Billadeau

    (Mayo Clinic)

  • Zhaoming Su

    (Sichuan University)

  • Da Jia

    (Sichuan University
    Sichuan University)

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.

Suggested Citation

  • Xin Yong & Guowen Jia & Qin Yang & Chunzhuang Zhou & Sitao Zhang & Huaqing Deng & Daniel D. Billadeau & Zhaoming Su & Da Jia, 2025. "Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58235-1
    DOI: 10.1038/s41467-025-58235-1
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