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TitleArchitecture of the human KICSTOR and GATOR1-KICSTOR complexes.
Journal, issue, pagesNat Struct Mol Biol, Vol. 32, Issue 12, Page 2587-2600, Year 2025
Publish dateNov 6, 2025
AuthorsFei Teng / Huan Zeng / Xinyi Mai / Shujun Chen / Lulu Wang / Zeming Feng / Shuyun Tian / Shan Wang / Goran Stjepanovic / Chun-Yan Lim / Ming-Yuan Su /
PubMed AbstractThe human KICSTOR complex, comprising KPTN, ITFG2, C12orf66 and the scaffolding protein SZT2, anchors the mTORC1 inhibitor GATOR1 to lysosomes. Mutations affecting KICSTOR subunits are associated ...The human KICSTOR complex, comprising KPTN, ITFG2, C12orf66 and the scaffolding protein SZT2, anchors the mTORC1 inhibitor GATOR1 to lysosomes. Mutations affecting KICSTOR subunits are associated with severe neurodevelopmental and epileptic disorders. Loss of KICSTOR mimics GATOR1 inactivation, resulting in constitutive mTORC1 activation, highlighting its critical role in nutrient sensing. Here, we used cryo-electron microscopy and computational modeling to determine the architectures of KICSTOR and the GATOR1-KICSTOR supercomplex. We show that SZT2 forms a crescent-shaped scaffold with repetitive tandem units, binding the ITFG2-KPTN heterodimer and C12orf66 at its C terminus. Structural and biochemical analyses revealed that GATOR1 binds the SZT2 N-terminal domain through NPRL3; disruption of this interaction hyperactivates mTORC1 and mislocalizes TFE3 independently of nutrient status. We further demonstrate the membrane-binding ability of KICSTOR, with SZT2 and C12orf66 preferentially interacting with negatively charged lipids-a requirement for lysosomal localization. These findings identify how KICSTOR positions GATOR1 on lysosomes to regulate nutrient-dependent mTORC1 signaling.
External linksNat Struct Mol Biol / PubMed:41198956
MethodsEM (single particle)
Resolution2.9 - 3.19 Å
Structure data

64665

9v0j

EMDB-64665, PDB-9v0j:
Cryo-EM structure of GATOR1-KICSTOR complex
Method: EM (single particle) / Resolution: 2.97 Å

64799

9v6e

EMDB-64799, PDB-9v6e:
Cryo-EM structure of human full length KICSTOR complex (state 1)
Method: EM (single particle) / Resolution: 3.19 Å

64827

9v80

EMDB-64827, PDB-9v80:
Cryo-EM structure of KICSTOR CCC complex (state 4)
Method: EM (single particle) / Resolution: 2.95 Å

64831

9v86

EMDB-64831, PDB-9v86:
Cryo-EM structure of KICSTOR CCC complex (state 3)
Method: EM (single particle) / Resolution: 3.04 Å

64877

9v9n

EMDB-64877, PDB-9v9n:
Cryo-EM structure of KICSTOR CCC complex (state 5)
Method: EM (single particle) / Resolution: 3.08 Å

64902

9van

EMDB-64902, PDB-9van:
Cryo-EM structure of human full length KICSTOR complex (state 2)
Method: EM (single particle) / Resolution: 2.9 Å

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / GAP / Lipid binding protein

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