PUBLICATION
Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome
- Authors
- Yong, X., Jia, G., Yang, Q., Zhou, C., Zhang, S., Deng, H., Billadeau, D.D., Su, Z., Jia, D.
- ID
- ZDB-PUB-250327-18
- Date
- 2025
- Source
- Nature communications 16: 29672967 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Protein Domains
- Animals
- Protein Binding
- Guanine Nucleotide Exchange Factors
- Models, Molecular
- Melanosomes/metabolism
- Melanosomes/ultrastructure
- Carrier Proteins
- Membrane Proteins/chemistry
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Hermanski-Pudlak Syndrome*/genetics
- Hermanski-Pudlak Syndrome*/metabolism
- Hermanski-Pudlak Syndrome*/pathology
- rab GTP-Binding Proteins*/genetics
- rab GTP-Binding Proteins*/metabolism
- Humans
- Mutation
- GTP Phosphohydrolases/chemistry
- GTP Phosphohydrolases/genetics
- GTP Phosphohydrolases/metabolism
- Cryoelectron Microscopy*
- HEK293 Cells
- Zebrafish*
- PubMed
- 40140412 Full text @ Nat. Commun.
Citation
Yong, X., Jia, G., Yang, Q., Zhou, C., Zhang, S., Deng, H., Billadeau, D.D., Su, Z., Jia, D. (2025) Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome. Nature communications. 16:29672967.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping