What question did this study set out to answer?

The study aims to elucidate the molecular architecture and function of the KICSTOR complex in mTORC1 regulation.

February 21, 2026

BPS2026 – Molecular architecture of KICSTOR in lysosomal membrane targeting and mTORC1 control

Key Points

The study aims to elucidate the molecular architecture and function of the KICSTOR complex in mTORC1 regulation.
Utilized cryogenic electron microscopy to create structural models of KICSTOR components.
Analyzed the binding interactions of KICSTOR proteins with lipids.
Investigated the effects of mutations in KICSTOR on mTORC1 activation.
KICSTOR anchoring is critical for GATOR1 localization to lysosomes.
Loss of any KICSTOR component results in continuous activation of mTORC1.
The N-terminal domain of SZT2 specifically binds Nprl3, a GATOR1 subunit.

Abstract

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.

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Cite This Study

Ming-Yuan Su (Sun,) studied this question.

synapsesocial.com/papers/69990df65b97ab4c14ac2bb1 https://doi.org/https://doi.org/10.1016/j.bpj.2025.11.2443

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