Biochemical and structural characterization of Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1)

Abstract

Lysosome-related organelles (LROs) play critical roles in diverse cellular processes, and their dysfunction is linked to genetic disorders such as Hermansky-Pudlak Syndrome (HPS). BLOC-1(Biogenesis of Lysosome-related Organelles Complex-1) is a key regulator of LRO biogenesis and intracellular vesicle trafficking. However, the molecular mechanisms governing BLOC-1 assembly and its function remain poorly understood. In this study, we present a biochemical and structural characterization of BLOC-1, revealing a curved, arc-shaped architecture. Our structural model demonstrates that this hetero-octameric complex is composed of two distinct hemicomplexes: BLOC1S2/5/7/8 and BLOC1S1/3/4/6. Cryo-EM 2D classification analysis shows that both hemicomplexes adopt extended rod-like structures but differ in length. The merging of these two hemicomplexes gives rise to BLOC-1's unique arc-like conformation. These findings provide critical insights into the molecular architecture of BLOC-1, advancing our understanding of its role in LRO biogenesis and vesicle trafficking.

Keywords: AlphaFold3; BLOC-1; Cryo-EM; HPS; LROs biogenesis.