Identification of the allosteric regulatory site of insulysin
Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits al...
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| Veröffentlicht in: | PLoS One 2011-06, Vol.6 (6), p.e20864-e20864 |
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| creator | Noinaj, Nicholas Bhasin, Sonia K Song, Eun Suk Scoggin, Kirsten E Juliano, Maria A Juliano, Luiz Hersh, Louis B Rodgers, David W |
| description | Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.
The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.
Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme. |
| doi_str_mv | 10.1371/journal.pone.0020864 |
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The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.
Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0020864</identifier><identifier>PMID: 21731629</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>60 APPLIED LIFE SCIENCES ; Activation ; Adenosine Triphosphate - analogs & derivatives ; Adenosine Triphosphate - metabolism ; Allosteric properties ; Allosteric Regulation ; Allosteric Site ; Alzheimer's disease ; Analysis ; Animals ; Aspartic proteases ; ATP ; Automation ; BASIC BIOLOGICAL SCIENCES ; Binding sites ; Biochemistry ; Biology ; Biophysics ; Chromatography ; CLEARANCE ; COMMUNICATIONS ; CONFORMATIONAL CHANGES ; CRYSTAL STRUCTURE ; Crystallography, X-Ray ; Datasets ; Diabetes ; DIMERS ; ELECTRON DENSITY ; Enzymatic activity ; ENZYME ACTIVITY ; ENZYMES ; INSULIN ; Insulysin ; Insulysin - chemistry ; Insulysin - metabolism ; KINETICS ; Life sciences ; Ligands ; Mass Spectrometry ; METABOLISM ; Models, Molecular ; Mutant Proteins - chemistry ; Mutant Proteins - metabolism ; MUTANTS ; Mutation - genetics ; Neurodegenerative diseases ; PEPTIDES ; Physiological aspects ; Polyphosphates ; Protein Binding ; Protein Multimerization ; Protein Structure, Secondary ; Proteins ; Proteolysis ; Proteolytic enzymes ; Rats ; Reaction kinetics ; RESIDUES ; Scientific imaging ; Spectrometry, Fluorescence ; SUBSTRATES ; Type 2 diabetes</subject><ispartof>PLoS One, 2011-06, Vol.6 (6), p.e20864-e20864</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Noinaj et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Noinaj et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c718t-7ae5959a4339460473f81753dedd20efebd71101fc97427f4a839272e90a1813</citedby><cites>FETCH-LOGICAL-c718t-7ae5959a4339460473f81753dedd20efebd71101fc97427f4a839272e90a1813</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123307/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123307/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21731629$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1040891$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><contributor>Gerrard, Juliet Ann</contributor><creatorcontrib>Noinaj, Nicholas</creatorcontrib><creatorcontrib>Bhasin, Sonia K</creatorcontrib><creatorcontrib>Song, Eun Suk</creatorcontrib><creatorcontrib>Scoggin, Kirsten E</creatorcontrib><creatorcontrib>Juliano, Maria A</creatorcontrib><creatorcontrib>Juliano, Luiz</creatorcontrib><creatorcontrib>Hersh, Louis B</creatorcontrib><creatorcontrib>Rodgers, David W</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Identification of the allosteric regulatory site of insulysin</title><title>PLoS One</title><addtitle>PLoS One</addtitle><description>Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.
The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.
Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Activation</subject><subject>Adenosine Triphosphate - analogs & derivatives</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Allosteric properties</subject><subject>Allosteric Regulation</subject><subject>Allosteric Site</subject><subject>Alzheimer's disease</subject><subject>Analysis</subject><subject>Animals</subject><subject>Aspartic proteases</subject><subject>ATP</subject><subject>Automation</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Biophysics</subject><subject>Chromatography</subject><subject>CLEARANCE</subject><subject>COMMUNICATIONS</subject><subject>CONFORMATIONAL CHANGES</subject><subject>CRYSTAL STRUCTURE</subject><subject>Crystallography, X-Ray</subject><subject>Datasets</subject><subject>Diabetes</subject><subject>DIMERS</subject><subject>ELECTRON DENSITY</subject><subject>Enzymatic activity</subject><subject>ENZYME ACTIVITY</subject><subject>ENZYMES</subject><subject>INSULIN</subject><subject>Insulysin</subject><subject>Insulysin - chemistry</subject><subject>Insulysin - metabolism</subject><subject>KINETICS</subject><subject>Life sciences</subject><subject>Ligands</subject><subject>Mass Spectrometry</subject><subject>METABOLISM</subject><subject>Models, Molecular</subject><subject>Mutant Proteins - chemistry</subject><subject>Mutant Proteins - metabolism</subject><subject>MUTANTS</subject><subject>Mutation - genetics</subject><subject>Neurodegenerative diseases</subject><subject>PEPTIDES</subject><subject>Physiological aspects</subject><subject>Polyphosphates</subject><subject>Protein Binding</subject><subject>Protein Multimerization</subject><subject>Protein Structure, Secondary</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Proteolytic enzymes</subject><subject>Rats</subject><subject>Reaction kinetics</subject><subject>RESIDUES</subject><subject>Scientific imaging</subject><subject>Spectrometry, Fluorescence</subject><subject>SUBSTRATES</subject><subject>Type 2 diabetes</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12LEzEUhgdR3LX6D0SLguJFa746SS5cWBY_CgsLungbspmTNiWd1CQj239vxs4uHdkLyUVC8pw357zJqaqXGM0x5fjjJnSx1X6-Cy3MESJI1OxRdYolJbOaIPr4aH1SPUtpg9CCirp-Wp0QzCmuiTytPi0baLOzzujsQjsNdprXMNXeh5QhOjONsOq8ziHup8ll6AnXps7vk2ufV0-s9gleDPOkuv7y-fri2-zy6uvy4vxyZjgWecY1LORCakapZDVinFqB-YI20DQEgYWbhmOMsDWSM8It04JKwglIpLHAdFK9PsjuSlZqKDwpTBErp6IoTarlgWiC3qhddFsd9ypop_5uhLhSOmZnPCgBjWVgBTIlGVMvtJYGUc4JbTQYLYvW2XBbd7OFxhR_ovYj0fFJ69ZqFX4rigmliBeBNweBYqFTyRTXzNqEtgWTFUYMCdnX9H64JYZfHaSsti4Z8F63ELqkSlVMSEp78u0_5MMODNRKlyJda0PJzfSa6pzxWohaMFao-QNUGQ1sXUkRrCv7o4APo4DCZLjNK92lpJY_vv8_e_VzzL47YtegfV6n4Lv-E6YxyA6giSGlCPb-ITBSfSPcuaH6RlBDI5SwV8ePeB909_PpH3vRAbI</recordid><startdate>20110624</startdate><enddate>20110624</enddate><creator>Noinaj, Nicholas</creator><creator>Bhasin, Sonia K</creator><creator>Song, Eun Suk</creator><creator>Scoggin, Kirsten E</creator><creator>Juliano, Maria A</creator><creator>Juliano, Luiz</creator><creator>Hersh, Louis B</creator><creator>Rodgers, David W</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>OTOTI</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110624</creationdate><title>Identification of the allosteric regulatory site of insulysin</title><author>Noinaj, Nicholas ; Bhasin, Sonia K ; Song, Eun Suk ; Scoggin, Kirsten E ; Juliano, Maria A ; Juliano, Luiz ; Hersh, Louis B ; Rodgers, David W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c718t-7ae5959a4339460473f81753dedd20efebd71101fc97427f4a839272e90a1813</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Activation</topic><topic>Adenosine Triphosphate - analogs & derivatives</topic><topic>Adenosine Triphosphate - metabolism</topic><topic>Allosteric properties</topic><topic>Allosteric Regulation</topic><topic>Allosteric Site</topic><topic>Alzheimer's disease</topic><topic>Analysis</topic><topic>Animals</topic><topic>Aspartic proteases</topic><topic>ATP</topic><topic>Automation</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>Binding sites</topic><topic>Biochemistry</topic><topic>Biology</topic><topic>Biophysics</topic><topic>Chromatography</topic><topic>CLEARANCE</topic><topic>COMMUNICATIONS</topic><topic>CONFORMATIONAL CHANGES</topic><topic>CRYSTAL STRUCTURE</topic><topic>Crystallography, X-Ray</topic><topic>Datasets</topic><topic>Diabetes</topic><topic>DIMERS</topic><topic>ELECTRON DENSITY</topic><topic>Enzymatic activity</topic><topic>ENZYME ACTIVITY</topic><topic>ENZYMES</topic><topic>INSULIN</topic><topic>Insulysin</topic><topic>Insulysin - chemistry</topic><topic>Insulysin - metabolism</topic><topic>KINETICS</topic><topic>Life sciences</topic><topic>Ligands</topic><topic>Mass Spectrometry</topic><topic>METABOLISM</topic><topic>Models, Molecular</topic><topic>Mutant Proteins - 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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of the allosteric regulatory site of insulysin</atitle><jtitle>PLoS One</jtitle><addtitle>PLoS One</addtitle><date>2011-06-24</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e20864</spage><epage>e20864</epage><pages>e20864-e20864</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.
The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.
Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21731629</pmid><doi>10.1371/journal.pone.0020864</doi><tpages>e20864</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | PLoS One, 2011-06, Vol.6 (6), p.e20864-e20864 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | 60 APPLIED LIFE SCIENCES Activation Adenosine Triphosphate - analogs & derivatives Adenosine Triphosphate - metabolism Allosteric properties Allosteric Regulation Allosteric Site Alzheimer's disease Analysis Animals Aspartic proteases ATP Automation BASIC BIOLOGICAL SCIENCES Binding sites Biochemistry Biology Biophysics Chromatography CLEARANCE COMMUNICATIONS CONFORMATIONAL CHANGES CRYSTAL STRUCTURE Crystallography, X-Ray Datasets Diabetes DIMERS ELECTRON DENSITY Enzymatic activity ENZYME ACTIVITY ENZYMES INSULIN Insulysin Insulysin - chemistry Insulysin - metabolism KINETICS Life sciences Ligands Mass Spectrometry METABOLISM Models, Molecular Mutant Proteins - chemistry Mutant Proteins - metabolism MUTANTS Mutation - genetics Neurodegenerative diseases PEPTIDES Physiological aspects Polyphosphates Protein Binding Protein Multimerization Protein Structure, Secondary Proteins Proteolysis Proteolytic enzymes Rats Reaction kinetics RESIDUES Scientific imaging Spectrometry, Fluorescence SUBSTRATES Type 2 diabetes |
| title | Identification of the allosteric regulatory site of insulysin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T08%3A08%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20the%20allosteric%20regulatory%20site%20of%20insulysin&rft.jtitle=PLoS%20One&rft.au=Noinaj,%20Nicholas&rft.aucorp=Argonne%20National%20Lab.%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2011-06-24&rft.volume=6&rft.issue=6&rft.spage=e20864&rft.epage=e20864&rft.pages=e20864-e20864&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0020864&rft_dat=%3Cgale_plos_%3EA476886844%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1304813875&rft_id=info:pmid/21731629&rft_galeid=A476886844&rft_doaj_id=oai_doaj_org_article_8edf4ef80c394c65aa9c037723daeca9&rfr_iscdi=true |