Architecture of the human KICSTOR and GATOR1-KICSTOR complexes

Area of Science:

• Cellular Biology
• Structural Biology
• Neuroscience

Background:

• The KICSTOR complex (KPTN, ITFG2, C12orf66, SZT2) is crucial for mTORC1 inhibition and nutrient sensing.
• Mutations in KICSTOR subunits are linked to severe neurodevelopmental and epileptic disorders.
• Loss of KICSTOR function leads to constitutive mTORC1 activation, similar to GATOR1 inactivation.

Purpose of the Study:

• To elucidate the architecture of the KICSTOR complex and the GATOR1-KICSTOR supercomplex.
• To understand the structural basis of KICSTOR's role in nutrient sensing and mTORC1 regulation.
• To investigate the mechanism of KICSTOR's lysosomal localization.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine complex structures.
• Computational modeling to analyze architectures.
• Biochemical analyses to study protein interactions and function.

Main Results:

• Determined the architectures of KICSTOR and the GATOR1-KICSTOR supercomplex.
• SZT2 forms a scaffold that binds KICSTOR subunits and interacts with GATOR1 via NPRL3.
• KICSTOR binds to negatively charged lipids, facilitating lysosomal localization and regulating mTORC1 signaling.

Conclusions:

• KICSTOR positions GATOR1 on lysosomes to control nutrient-dependent mTORC1 signaling.
• Disruption of the GATOR1-SZT2 interaction leads to mTORC1 hyperactivation and TFE3 mislocalization.
• Structural insights explain KICSTOR's function in nutrient sensing and its link to neurodevelopmental disorders.