High-resolution cryo-EM structure reveals how human cells activate key trafficking protein RAB7A

RAB7A plays a central role in the final stages of autophagy, facilitating autophagosome-lysosome fusion, lysosome positioning, and cargo degradation. Its activation by guanine nucleotide exchange factors (GEFs) such as the MON1A-CCZ1 (MC1) complex is essential for maintaining cellular homeostasis. While previous studies have characterized fungal and insect homologs of the MC1 complex, the structural basis for RAB7A activation in mammals remained unclear.

In a recent study published in Life Metabolism, researchers from Prof. Shiqian Qi’s lab at Sichuan University and Prof. Jiawei Wang’s lab at Tsinghua University resolved a longstanding question in cellular biology: how human cells activate RAB7A, a master regulator of late endosome and lysosome function, through a conserved GEF complex. The study reports the first high-resolution cryo-electron microscopy (cryo-EM) structure of the human MON1A-CCZ1 (HsMC1) complex bound to nucleotide-free RAB7A at a resolution of 2.85 Å, shedding light on a critical step in autophagy and intracellular trafficking (Figure 1).

Beyond structural insight, the study has potential clinical relevance. Defects in RAB7A activity are associated with neurodegenerative diseases and lysosomal storage disorders. By delineating how RAB7A is activated in human cells, this research opens new avenues for targeted therapeutics aimed at modulating autophagic flux.