Molecular mechanism of S -adenosylmethionine sensing by SAMTOR in mTORC1 signaling
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...
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| Veröffentlicht in: | Science advances 2022-07, Vol.8 (26), p.eabn3868-eabn3868 |
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| creator | Tang, Xin Zhang, Yifan Wang, Guanchao Zhang, Chunxiao Wang, Fang Shi, Jiawen Zhang, Tianlong Ding, Jianping |
| description | 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. |
| doi_str_mv | 10.1126/sciadv.abn3868 |
| format | Article |
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-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.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abn3868</identifier><identifier>PMID: 35776786</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Biomedicine and Life Sciences ; Drosophila melanogaster - metabolism ; GTPase-Activating Proteins - metabolism ; Mechanistic Target of Rapamycin Complex 1 - metabolism ; Molecular Biology ; S-Adenosylmethionine ; SciAdv r-articles ; Signal Transduction ; Structural Biology</subject><ispartof>Science advances, 2022-07, Vol.8 (26), p.eabn3868-eabn3868</ispartof><rights>Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2022 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-c227e6567941364a17acdab977c53251a4cf7312430d8f859429dfb19f6b40363</citedby><cites>FETCH-LOGICAL-c391t-c227e6567941364a17acdab977c53251a4cf7312430d8f859429dfb19f6b40363</cites><orcidid>0000-0002-3559-0974 ; 0000-0001-7812-8854 ; 0000-0003-1952-9185 ; 0000-0002-3052-074X ; 0000-0002-0702-465X ; 0000-0002-1207-6032 ; 0000-0001-7029-7346</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883374/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883374/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,27905,27906,53772,53774</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35776786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tang, Xin</creatorcontrib><creatorcontrib>Zhang, Yifan</creatorcontrib><creatorcontrib>Wang, Guanchao</creatorcontrib><creatorcontrib>Zhang, Chunxiao</creatorcontrib><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Shi, Jiawen</creatorcontrib><creatorcontrib>Zhang, Tianlong</creatorcontrib><creatorcontrib>Ding, Jianping</creatorcontrib><title>Molecular mechanism of S -adenosylmethionine sensing by SAMTOR in mTORC1 signaling</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>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.</description><subject>Animals</subject><subject>Biomedicine and Life Sciences</subject><subject>Drosophila melanogaster - metabolism</subject><subject>GTPase-Activating Proteins - metabolism</subject><subject>Mechanistic Target of Rapamycin Complex 1 - metabolism</subject><subject>Molecular Biology</subject><subject>S-Adenosylmethionine</subject><subject>SciAdv r-articles</subject><subject>Signal Transduction</subject><subject>Structural Biology</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1rAjEUDKWlivXaY8mxl7X52iR7KiL9AkVQew7ZbFZTdhO7WQX_fbdoxZ7mwcybN7wB4B6jEcaEP0XjdLEf6dxTyeUV6BMq0oSkTF5fzD0wjPELIYQZ5ynObkGPpkJwIXkfLGahsmZX6QbW1my0d7GGoYRLmOjC-hAPVW3bjQveeQuj9dH5NcwPcDmereYL6DysO5xgGN3a66pj78BNqatohyccgM_Xl9XkPZnO3z4m42liaIbbxBAiLE-5yBimnGkstCl0nglhUkpSrJkpBcWEUVTIUqYZI1lR5jgrec4Q5XQAno--211e28JY3za6UtvG1bo5qKCd-s94t1HrsFcYSUmpYJ3D48mhCd87G1tVu2hsVWlvwy4qwiXDCDEhO-noKDVNiLGx5fkORuq3DHUsQ53K6BYeLtOd5X-vpz89RYb8</recordid><startdate>202207</startdate><enddate>202207</enddate><creator>Tang, Xin</creator><creator>Zhang, Yifan</creator><creator>Wang, Guanchao</creator><creator>Zhang, Chunxiao</creator><creator>Wang, Fang</creator><creator>Shi, Jiawen</creator><creator>Zhang, Tianlong</creator><creator>Ding, Jianping</creator><general>American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3559-0974</orcidid><orcidid>https://orcid.org/0000-0001-7812-8854</orcidid><orcidid>https://orcid.org/0000-0003-1952-9185</orcidid><orcidid>https://orcid.org/0000-0002-3052-074X</orcidid><orcidid>https://orcid.org/0000-0002-0702-465X</orcidid><orcidid>https://orcid.org/0000-0002-1207-6032</orcidid><orcidid>https://orcid.org/0000-0001-7029-7346</orcidid></search><sort><creationdate>202207</creationdate><title>Molecular mechanism of S -adenosylmethionine sensing by SAMTOR in mTORC1 signaling</title><author>Tang, Xin ; Zhang, Yifan ; Wang, Guanchao ; Zhang, Chunxiao ; Wang, Fang ; Shi, Jiawen ; Zhang, Tianlong ; Ding, Jianping</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-c227e6567941364a17acdab977c53251a4cf7312430d8f859429dfb19f6b40363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Biomedicine and Life Sciences</topic><topic>Drosophila melanogaster - metabolism</topic><topic>GTPase-Activating Proteins - metabolism</topic><topic>Mechanistic Target of Rapamycin Complex 1 - metabolism</topic><topic>Molecular Biology</topic><topic>S-Adenosylmethionine</topic><topic>SciAdv r-articles</topic><topic>Signal Transduction</topic><topic>Structural Biology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tang, Xin</creatorcontrib><creatorcontrib>Zhang, Yifan</creatorcontrib><creatorcontrib>Wang, Guanchao</creatorcontrib><creatorcontrib>Zhang, Chunxiao</creatorcontrib><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Shi, Jiawen</creatorcontrib><creatorcontrib>Zhang, Tianlong</creatorcontrib><creatorcontrib>Ding, Jianping</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tang, Xin</au><au>Zhang, Yifan</au><au>Wang, Guanchao</au><au>Zhang, Chunxiao</au><au>Wang, Fang</au><au>Shi, Jiawen</au><au>Zhang, Tianlong</au><au>Ding, Jianping</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular mechanism of S -adenosylmethionine sensing by SAMTOR in mTORC1 signaling</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2022-07</date><risdate>2022</risdate><volume>8</volume><issue>26</issue><spage>eabn3868</spage><epage>eabn3868</epage><pages>eabn3868-eabn3868</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><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.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>35776786</pmid><doi>10.1126/sciadv.abn3868</doi><orcidid>https://orcid.org/0000-0002-3559-0974</orcidid><orcidid>https://orcid.org/0000-0001-7812-8854</orcidid><orcidid>https://orcid.org/0000-0003-1952-9185</orcidid><orcidid>https://orcid.org/0000-0002-3052-074X</orcidid><orcidid>https://orcid.org/0000-0002-0702-465X</orcidid><orcidid>https://orcid.org/0000-0002-1207-6032</orcidid><orcidid>https://orcid.org/0000-0001-7029-7346</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biomedicine and Life Sciences Drosophila melanogaster - metabolism GTPase-Activating Proteins - metabolism Mechanistic Target of Rapamycin Complex 1 - metabolism Molecular Biology S-Adenosylmethionine SciAdv r-articles Signal Transduction Structural Biology |
| title | Molecular mechanism of S -adenosylmethionine sensing by SAMTOR in mTORC1 signaling |
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