The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction
Serine phosphorylations on insulin receptor substrate 1 (IRS-1) by diverse kinases aoccur widely during obesity-, stress-, and inflammation-induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS-1, which is directly C-terminal t...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2024-04, Vol.121 (17), p.e2401716121 |
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| creator | Woo, Ju Rang Bae, Seung-Hyun Wales, Thomas E Engen, John R Lee, Jongsoon Jang, Hyonchol Park, SangYoun |
| description | Serine phosphorylations on insulin receptor substrate 1 (IRS-1) by diverse kinases aoccur widely during obesity-, stress-, and inflammation-induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation. |
| doi_str_mv | 10.1073/pnas.2401716121 |
| format | Article |
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In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2401716121</identifier><identifier>PMID: 38625937</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>AKT protein ; Animals ; Binding ; Biological Sciences ; Cell Line ; Dephosphorylation ; Deuterium ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 ; Glutamates ; Humans ; Hydrogen-deuterium exchange ; Insulin ; Insulin - metabolism ; Insulin receptor substrate 1 ; Insulin Receptor Substrate Proteins - genetics ; Insulin Receptor Substrate Proteins - metabolism ; Insulin receptors ; Insulin Resistance ; Kinases ; Mass spectrometry ; Mass spectroscopy ; Mice ; Phosphoproteins - metabolism ; Phosphorylation ; Receptor, Insulin - metabolism ; Receptors ; Serine ; Serine - metabolism ; Substrates ; Surface plasmon resonance</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2024-04, Vol.121 (17), p.e2401716121</ispartof><rights>Copyright National Academy of Sciences Apr 23, 2024</rights><rights>Copyright © 2024 the Author(s). Published by PNAS. 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c335t-b0799f91494cb5298d2afb12e09aa510f883e59e6d2d83beb796511fb8e0c8df3</cites><orcidid>0000-0002-6918-9476 ; 0000-0002-6593-0036 ; 0000-0002-0891-5059 ; 0000-0003-1436-457X</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/PMC11046688/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11046688/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38625937$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Woo, Ju Rang</creatorcontrib><creatorcontrib>Bae, Seung-Hyun</creatorcontrib><creatorcontrib>Wales, Thomas E</creatorcontrib><creatorcontrib>Engen, John R</creatorcontrib><creatorcontrib>Lee, Jongsoon</creatorcontrib><creatorcontrib>Jang, Hyonchol</creatorcontrib><creatorcontrib>Park, SangYoun</creatorcontrib><title>The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Serine phosphorylations on insulin receptor substrate 1 (IRS-1) by diverse kinases aoccur widely during obesity-, stress-, and inflammation-induced conditions in models of insulin resistance and type 2 diabetes. In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation.</description><subject>AKT protein</subject><subject>Animals</subject><subject>Binding</subject><subject>Biological Sciences</subject><subject>Cell Line</subject><subject>Dephosphorylation</subject><subject>Deuterium</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2</subject><subject>Glutamates</subject><subject>Humans</subject><subject>Hydrogen-deuterium exchange</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin receptor substrate 1</subject><subject>Insulin Receptor Substrate Proteins - genetics</subject><subject>Insulin Receptor Substrate Proteins - metabolism</subject><subject>Insulin receptors</subject><subject>Insulin Resistance</subject><subject>Kinases</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Mice</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Receptor, Insulin - metabolism</subject><subject>Receptors</subject><subject>Serine</subject><subject>Serine - metabolism</subject><subject>Substrates</subject><subject>Surface plasmon resonance</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctLxDAQxoMouq6evUnBi5e6M3m0yUlEfCwIio9zSNvUrXSTNekK_vdmcX0ehgz5fvMxw0fIAcIJQskmC2fiCeWAJRZIcYOMEBTmBVewSUYAtMwlp3yH7Mb4AgBKSNgmO0wWVChWjsjT48xm0YbO2Wwx8zFVeO_N0HkXs85lQ5Kn9w85ZnfT-6zxc5M-TRX8sxm-FOOa1CV6sMHUq9E9stWaPtr99TsmT5cXj-fX-c3t1fT87CavGRNDXkGpVKuQK15XgirZUNNWSC0oYwRCKyWzQtmioY1kla1KVQjEtpIWatm0bExOP30Xy2pum9q6IZheL0I3N-Fde9Ppv4rrZvrZv2lE4EWR7MfkeO0Q_OvSxkHPu1jbvjfO-mXUDDgwioKJhB79Q1_8Mrh034qSyCmUmKjJJ1UHH2Ow7fc2CHqVmV5lpn8ySxOHv4_45r9CYh95JZGi</recordid><startdate>20240423</startdate><enddate>20240423</enddate><creator>Woo, Ju Rang</creator><creator>Bae, Seung-Hyun</creator><creator>Wales, Thomas E</creator><creator>Engen, John R</creator><creator>Lee, Jongsoon</creator><creator>Jang, Hyonchol</creator><creator>Park, SangYoun</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6918-9476</orcidid><orcidid>https://orcid.org/0000-0002-6593-0036</orcidid><orcidid>https://orcid.org/0000-0002-0891-5059</orcidid><orcidid>https://orcid.org/0000-0003-1436-457X</orcidid></search><sort><creationdate>20240423</creationdate><title>The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction</title><author>Woo, Ju Rang ; 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In this study, we define a region within the human IRS-1, which is directly C-terminal to the PTB domain encompassing numerous serine phosphorylation sites including Ser307 (mouse Ser302) and Ser312 (mouse 307) creating a phosphorylation insulin resistance (PIR) domain. We demonstrate that the IRS-1 PTB-PIR with its unphosphorylated serine residues interacts with the insulin receptor (IR) but loses the IR-binding when they are phosphorylated. Surface plasmon resonance studies further confirm that the PTB-PIR binds stronger to IR than just the PTB domain, and that phosphorylations at Ser307, Ser312, Ser315, and Ser323 within the PIR domain result in abrogating the binding. Insulin-responsive cells containing the mutant IRS-1 with all these four serines changed into glutamates to mimic phosphorylations show decreased levels of phosphorylations in IR, IRS-1, and AKT compared to the wild-type IRS-1. Hydrogen-deuterium exchange mass spectrometry experiments indicating the PIR domain interacting with the N-terminal lobe and the hinge regions of the IR kinase domain further suggest the possibility that the IRS-1 PIR domain protects the IR from the PTP1B-mediated dephosphorylation.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>38625937</pmid><doi>10.1073/pnas.2401716121</doi><orcidid>https://orcid.org/0000-0002-6918-9476</orcidid><orcidid>https://orcid.org/0000-0002-6593-0036</orcidid><orcidid>https://orcid.org/0000-0002-0891-5059</orcidid><orcidid>https://orcid.org/0000-0003-1436-457X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | AKT protein Animals Binding Biological Sciences Cell Line Dephosphorylation Deuterium Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 Glutamates Humans Hydrogen-deuterium exchange Insulin Insulin - metabolism Insulin receptor substrate 1 Insulin Receptor Substrate Proteins - genetics Insulin Receptor Substrate Proteins - metabolism Insulin receptors Insulin Resistance Kinases Mass spectrometry Mass spectroscopy Mice Phosphoproteins - metabolism Phosphorylation Receptor, Insulin - metabolism Receptors Serine Serine - metabolism Substrates Surface plasmon resonance |
| title | The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction |
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