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

Xin Yong, Guowen Jia, Qin Yang, Chunzhuang Zhou, Sitao Zhang, Huaqing Deng, Daniel D. Billadeau, Zhaoming Su () and Da Jia ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58235-1

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