The KICSTOR complex is crucial for anchoring the mTORC1 repressor GATOR1 to lysosomes, with mutations causing severe neurodevelopmental and epileptic disorders. KICSTOR consists of KPTN, ITFG2, C12orf66, and the large scaffolding protein SZT2. Loss of any single component leads to continuous mTORC1 activation, highlighting KICSTOR’s essential role in nutrient sensing and mTORC1 regulation. Structural models generated using cryogenic electron microscopy show SZT2 forming a stalk-like backbone that anchors the other proteins. GATOR1’s subunit Nprl3 binds specifically to SZT2’s N-terminal domain. Additionally, SZT2 and C12orf66 bind to negatively charged lipids, a feature vital for lysosomal membrane localization. These findings illustrate how KICSTOR scaffolds GATOR1 on lysosomes, enabling nutrient-dependent regulation of mTORC1 and offering key insights into molecular mechanisms underlying related neurodevelopmental disorders.
Ming-Yuan Su (Sun,) studied this question.