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SAMTOR 在 mTORC1 信号中感知 - 腺苷甲硫氨酸的分子机制。

Molecular mechanism of -adenosylmethionine sensing by SAMTOR in mTORC1 signaling.

机构信息

State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.

School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.

出版信息

Sci Adv. 2022 Jul;8(26):eabn3868. doi: 10.1126/sciadv.abn3868. Epub 2022 Jul 1.

DOI:10.1126/sciadv.abn3868
PMID:35776786
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10883374/
Abstract

The mechanistic target of rapamycin-mLST8-raptor complex (mTORC1) functions as a central regulator of cell growth and metabolism in response to changes in nutrient signals such as amino acids. SAMTOR is an -adenosylmethionine (SAM) sensor, which regulates the mTORC1 activity through its interaction with the GTPase-activating protein activity toward Rags-1 (GATOR1)-KPTN, ITFG2, C12orf66 and SZT2-containing regulator (KICSTOR) complex. In this work, we report the crystal structures of SAMTOR in apo form and in complex with SAM. SAMTOR comprises an N-terminal helical domain and a C-terminal SAM-dependent methyltransferase (MTase) domain. The MTase domain contains the SAM-binding site and the potential GATOR1-KICSTOR-binding site. The helical domain functions as a molecular switch, which undergoes conformational change upon SAM binding and thereby modulates the interaction of SAMTOR with GATOR1-KICSTOR. The functional roles of the key residues and the helical domain are validated by functional assays. Our structural and functional data together reveal the molecular mechanism of the SAM sensing of SAMTOR and its functional role in mTORC1 signaling.

摘要

雷帕霉素靶蛋白-mLST8-雷帕霉素复合物（mTORC1）作为细胞生长和代谢的中央调节剂，可响应营养信号（如氨基酸）的变化而发挥作用。SAMTOR 是一种 - 腺苷甲硫氨酸（SAM）传感器，通过与 GTPase 激活蛋白活性向 Rag 蛋白-1（GATOR1）-KPTN、ITFG2、C12orf66 和 SZT2 组成的调节剂（KICSTOR）复合物相互作用，调节 mTORC1 活性。在这项工作中，我们报告了 SAMTOR 在 apo 形式和与 SAM 复合物中的晶体结构。SAMTOR 由一个 N 端螺旋结构域和一个 C 端 SAM 依赖性甲基转移酶（MTase）结构域组成。MTase 结构域包含 SAM 结合位点和潜在的 GATOR1-KICSTOR 结合位点。螺旋结构域作为分子开关，在 SAM 结合后发生构象变化，从而调节 SAMTOR 与 GATOR1-KICSTOR 的相互作用。通过功能测定验证了关键残基和螺旋结构域的功能作用。我们的结构和功能数据共同揭示了 SAMTOR 对 SAM 的分子感应机制及其在 mTORC1 信号中的功能作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/69edad6de797/sciadv.abn3868-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/69bdc6305ca1/sciadv.abn3868-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/704d5e5ee5be/sciadv.abn3868-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/bb9ae0c05807/sciadv.abn3868-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/69edad6de797/sciadv.abn3868-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/69bdc6305ca1/sciadv.abn3868-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/704d5e5ee5be/sciadv.abn3868-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/bb9ae0c05807/sciadv.abn3868-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/876b/10883374/69edad6de797/sciadv.abn3868-f4.jpg

相似文献

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Molecular mechanism of -adenosylmethionine sensing by SAMTOR in mTORC1 signaling.

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[2]
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[3]
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[4]
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[8]
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[9]
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引用本文的文献

[1]
mTORC1 senses glutamine and other amino acids through GCN2.

EMBO J. 2025-7-21

[2]
The Molecular Basis of Amino Acids Sensing.

Adv Sci (Weinh). 2025-7

[3]
Mechanisms and rationales of SAM homeostasis.

Trends Biochem Sci. 2025-3

[4]
Multi-Omics Approach Reveals Genes and Pathways Affected in Miller-Dieker Syndrome.

Mol Neurobiol. 2025-4

[5]
The role of amino acids in skeletal muscle health and sarcopenia: A narrative review.

J Biomed Res. 2024-10-22

[6]
Ragopathies and the rising influence of RagGTPases on human diseases.

Nat Commun. 2024-7-10

[7]
Structures and Functions of the Human GATOR1 Complex.

Subcell Biochem. 2024

[8]
An evolutionary mechanism to assimilate new nutrient sensors into the mTORC1 pathway.

Nat Commun. 2024-3-21

[9]
PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Cell Metab. 2023-12-5

[10]
The post-translational regulation of transcription factor EB (TFEB) in health and disease.

EMBO Rep. 2023-11-6

本文引用的文献

[1]
Cul4A-DDB1-mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine.

J Clin Invest. 2021-11-1

[2]
Highly accurate protein structure prediction for the human proteome.

Nature. 2021-8

[3]
SAR1B senses leucine levels to regulate mTORC1 signalling.

Nature. 2021-8

[4]
Duodenal-jejunal bypass maintains hepatic S-adenosylmethionine/S-homocysteine ratio in diet-induced obese rats.

Surg Obes Relat Dis. 2021-7

[5]
Sensing and Signaling of Methionine Metabolism.

Metabolites. 2021-1-31

[6]
CBS and MAT2A improve methionine-mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation.

Cell Prolif. 2021-1

[7]
Glutamine and asparagine activate mTORC1 independently of Rag GTPases.

J Biol Chem. 2020-2-4

[8]
mTOR at the nexus of nutrition, growth, ageing and disease.

Nat Rev Mol Cell Biol. 2020-1-14

[9]
DALI and the persistence of protein shape.

Protein Sci. 2019-11-5

[10]
Architecture of human Rag GTPase heterodimers and their complex with mTORC1.

Science. 2019-10-11

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