RAB7HD/C5orf51 stabilizes newly synthesized RAB7A and facilitates its GTP loading

RAB GTPases are essential molecular switches governing eukaryotic vesicular trafficking by cycling between active GTP-bound and inactive GDP-bound states. While conformational changes facilitate their function, exposure of the hydrophobic switch regions presents a risk, potentially leading to toxic aggregation and degradation, a process increasingly recognized as RAB quality control. In this study, we identified RAB7HD/C5orf51 as a novel RAB7A partner that plays a crucial role in RAB quality control. C5orf51 strongly binds to newly translated, guanine nucleotide-free (apo) RAB7A and acts as a specialized chaperone to maintain its solubility, thereby preventing aggregation. Furthermore, we determined the crystal structure of the C5orf51-apo RAB7A complex at 3.36 Å resolution, revealing a specific RAB7A intermediate. This structural and functional evidence provides new molecular insights into the initial regulation and quality control of RAB proteins, ensuring their proper folding and availability for vesicular trafficking.