Characterization of the role of Kunitz‐type protease inhibitor domain in dimerization of amyloid precursor protein
A major difference between amyloid precursor protein (APP) isoforms (APP695 and APP751) is the existence of a Kunitz type protease inhibitor (KPI) domain which has a significant impact on the homo‐ and hetero‐dimerization of APP isoforms. However, the exact molecular mechanisms of dimer formation re...
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Veröffentlicht in: | Journal of computational chemistry 2023-06, Vol.44 (15), p.1437-1445 |
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creator | Byun, Jinyoung Vellampatti, Srivithya Chatterjee, Prathit Hwang, Sun Ha Kim, Byoung Choul Lee, Juyong |
description | A major difference between amyloid precursor protein (APP) isoforms (APP695 and APP751) is the existence of a Kunitz type protease inhibitor (KPI) domain which has a significant impact on the homo‐ and hetero‐dimerization of APP isoforms. However, the exact molecular mechanisms of dimer formation remain elusive. To characterize the role of the KPI domain in APP dimerization, we performed a single molecule pull down (SiMPull) assay where homo‐dimerization between tethered APP molecules and soluble APP molecules was highly preferred regardless of the type of APP isoforms, while hetero‐dimerization between tethered APP751 molecules and soluble APP695 molecules was limited. We further investigated the domain level APP‐APP interactions using coarse‐grained models with the Martini force field. Though the model initial ternary complexes (KPI‐E1, KPI‐KPI, KPI‐E2, E1‐E1, E2‐E2, and E1‐E2) generated using HADDOCK (HD) and AlphaFold2 (AF2), the binding free energy profiles and the binding affinities of the domain combinations were investigated via the umbrella sampling with Martini force field. Additionally, membrane‐bound microenvironments at the domain level were modeled. As a result, it was revealed that the KPI domain has a stronger attractive interaction with itself than the E1 and E2 domains, as reported elsewhere. Thus, the KPI domain of APP751 may form additional attractive interactions with E1, E2 and the KPI domain itself, whereas it is absent in APP695. In conclusion, we found that the APP751 homo‐dimer formation is predominant than the homodimerization in APP695, which is facilitated by the presence of the KPI domain. |
doi_str_mv | 10.1002/jcc.27100 |
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However, the exact molecular mechanisms of dimer formation remain elusive. To characterize the role of the KPI domain in APP dimerization, we performed a single molecule pull down (SiMPull) assay where homo‐dimerization between tethered APP molecules and soluble APP molecules was highly preferred regardless of the type of APP isoforms, while hetero‐dimerization between tethered APP751 molecules and soluble APP695 molecules was limited. We further investigated the domain level APP‐APP interactions using coarse‐grained models with the Martini force field. Though the model initial ternary complexes (KPI‐E1, KPI‐KPI, KPI‐E2, E1‐E1, E2‐E2, and E1‐E2) generated using HADDOCK (HD) and AlphaFold2 (AF2), the binding free energy profiles and the binding affinities of the domain combinations were investigated via the umbrella sampling with Martini force field. Additionally, membrane‐bound microenvironments at the domain level were modeled. As a result, it was revealed that the KPI domain has a stronger attractive interaction with itself than the E1 and E2 domains, as reported elsewhere. Thus, the KPI domain of APP751 may form additional attractive interactions with E1, E2 and the KPI domain itself, whereas it is absent in APP695. In conclusion, we found that the APP751 homo‐dimer formation is predominant than the homodimerization in APP695, which is facilitated by the presence of the KPI domain.</description><identifier>ISSN: 0192-8651</identifier><identifier>EISSN: 1096-987X</identifier><identifier>DOI: 10.1002/jcc.27100</identifier><identifier>PMID: 36988355</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>AlphaFold2 ; Amyloid beta-Protein Precursor - metabolism ; amyloid precursor protein ; Binding ; Dimerization ; Dimers ; Domains ; Free energy ; Precursors ; Protease ; Protease Inhibitors ; Protein A ; Protein Domains ; Protein Isoforms - metabolism ; Proteins ; protein–protein interaction ; single molecule pull down assay</subject><ispartof>Journal of computational chemistry, 2023-06, Vol.44 (15), p.1437-1445</ispartof><rights>2023 Wiley Periodicals LLC.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3530-57cb6051ed34760d0814586f397924be904a4d514d659601f6ba0ffeb636a7f83</citedby><cites>FETCH-LOGICAL-c3530-57cb6051ed34760d0814586f397924be904a4d514d659601f6ba0ffeb636a7f83</cites><orcidid>0000-0003-1174-4358</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcc.27100$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcc.27100$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36988355$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Byun, Jinyoung</creatorcontrib><creatorcontrib>Vellampatti, Srivithya</creatorcontrib><creatorcontrib>Chatterjee, Prathit</creatorcontrib><creatorcontrib>Hwang, Sun Ha</creatorcontrib><creatorcontrib>Kim, Byoung Choul</creatorcontrib><creatorcontrib>Lee, Juyong</creatorcontrib><title>Characterization of the role of Kunitz‐type protease inhibitor domain in dimerization of amyloid precursor protein</title><title>Journal of computational chemistry</title><addtitle>J Comput Chem</addtitle><description>A major difference between amyloid precursor protein (APP) isoforms (APP695 and APP751) is the existence of a Kunitz type protease inhibitor (KPI) domain which has a significant impact on the homo‐ and hetero‐dimerization of APP isoforms. However, the exact molecular mechanisms of dimer formation remain elusive. To characterize the role of the KPI domain in APP dimerization, we performed a single molecule pull down (SiMPull) assay where homo‐dimerization between tethered APP molecules and soluble APP molecules was highly preferred regardless of the type of APP isoforms, while hetero‐dimerization between tethered APP751 molecules and soluble APP695 molecules was limited. We further investigated the domain level APP‐APP interactions using coarse‐grained models with the Martini force field. Though the model initial ternary complexes (KPI‐E1, KPI‐KPI, KPI‐E2, E1‐E1, E2‐E2, and E1‐E2) generated using HADDOCK (HD) and AlphaFold2 (AF2), the binding free energy profiles and the binding affinities of the domain combinations were investigated via the umbrella sampling with Martini force field. Additionally, membrane‐bound microenvironments at the domain level were modeled. As a result, it was revealed that the KPI domain has a stronger attractive interaction with itself than the E1 and E2 domains, as reported elsewhere. Thus, the KPI domain of APP751 may form additional attractive interactions with E1, E2 and the KPI domain itself, whereas it is absent in APP695. In conclusion, we found that the APP751 homo‐dimer formation is predominant than the homodimerization in APP695, which is facilitated by the presence of the KPI domain.</description><subject>AlphaFold2</subject><subject>Amyloid beta-Protein Precursor - metabolism</subject><subject>amyloid precursor protein</subject><subject>Binding</subject><subject>Dimerization</subject><subject>Dimers</subject><subject>Domains</subject><subject>Free energy</subject><subject>Precursors</subject><subject>Protease</subject><subject>Protease Inhibitors</subject><subject>Protein A</subject><subject>Protein Domains</subject><subject>Protein Isoforms - metabolism</subject><subject>Proteins</subject><subject>protein–protein interaction</subject><subject>single molecule pull down assay</subject><issn>0192-8651</issn><issn>1096-987X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc2O0zAQxy0EoqVw4AVQJC7sIe04jh37iCJ2-ViJC0jcLCeZqK6SuNiOVt3TPgLPyJPgfoAEEiePrN_8ZjR_Ql5SWFOAYrNr23VRpfIRWVJQIley-vaYLIGqIpeC0wV5FsIOABgX5VOyYEJJyThfklhvjTdtRG_vTbRuylyfxS1m3g14rD_Nk433Px9-xMMes713EU3AzE5b29jofNa50dgpfWSdHf_SmPEwONulJmxnHxJ7arfTc_KkN0PAF5d3Rb5ev_tSv89vP998qN_e5i3jDHJetY0ATrFjZSWgA0lLLkXPVKWKskEFpSk7TstOcCWA9qIx0PfYCCZM1Uu2Im_O3jT3-4wh6tGGFofBTOjmoIvk4VAwAQl9_Q-6c7Of0na6kMDLopLqSF2dqda7EDz2eu_taPxBU9DHKHSKQp-iSOyri3FuRuz-kL9vn4DNGbizAx7-b9If6_qs_AVCVJQ6</recordid><startdate>20230605</startdate><enddate>20230605</enddate><creator>Byun, Jinyoung</creator><creator>Vellampatti, Srivithya</creator><creator>Chatterjee, Prathit</creator><creator>Hwang, Sun Ha</creator><creator>Kim, Byoung Choul</creator><creator>Lee, Juyong</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</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>JQ2</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-1174-4358</orcidid></search><sort><creationdate>20230605</creationdate><title>Characterization of the role of Kunitz‐type protease inhibitor domain in dimerization of amyloid precursor protein</title><author>Byun, Jinyoung ; Vellampatti, Srivithya ; Chatterjee, Prathit ; Hwang, Sun Ha ; Kim, Byoung Choul ; Lee, Juyong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3530-57cb6051ed34760d0814586f397924be904a4d514d659601f6ba0ffeb636a7f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>AlphaFold2</topic><topic>Amyloid beta-Protein Precursor - metabolism</topic><topic>amyloid precursor protein</topic><topic>Binding</topic><topic>Dimerization</topic><topic>Dimers</topic><topic>Domains</topic><topic>Free energy</topic><topic>Precursors</topic><topic>Protease</topic><topic>Protease Inhibitors</topic><topic>Protein A</topic><topic>Protein Domains</topic><topic>Protein Isoforms - metabolism</topic><topic>Proteins</topic><topic>protein–protein interaction</topic><topic>single molecule pull down assay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Byun, Jinyoung</creatorcontrib><creatorcontrib>Vellampatti, Srivithya</creatorcontrib><creatorcontrib>Chatterjee, Prathit</creatorcontrib><creatorcontrib>Hwang, Sun Ha</creatorcontrib><creatorcontrib>Kim, Byoung Choul</creatorcontrib><creatorcontrib>Lee, Juyong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Computer Science Collection</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of computational chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Byun, Jinyoung</au><au>Vellampatti, Srivithya</au><au>Chatterjee, Prathit</au><au>Hwang, Sun Ha</au><au>Kim, Byoung Choul</au><au>Lee, Juyong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of the role of Kunitz‐type protease inhibitor domain in dimerization of amyloid precursor protein</atitle><jtitle>Journal of computational chemistry</jtitle><addtitle>J Comput Chem</addtitle><date>2023-06-05</date><risdate>2023</risdate><volume>44</volume><issue>15</issue><spage>1437</spage><epage>1445</epage><pages>1437-1445</pages><issn>0192-8651</issn><eissn>1096-987X</eissn><abstract>A major difference between amyloid precursor protein (APP) isoforms (APP695 and APP751) is the existence of a Kunitz type protease inhibitor (KPI) domain which has a significant impact on the homo‐ and hetero‐dimerization of APP isoforms. However, the exact molecular mechanisms of dimer formation remain elusive. To characterize the role of the KPI domain in APP dimerization, we performed a single molecule pull down (SiMPull) assay where homo‐dimerization between tethered APP molecules and soluble APP molecules was highly preferred regardless of the type of APP isoforms, while hetero‐dimerization between tethered APP751 molecules and soluble APP695 molecules was limited. We further investigated the domain level APP‐APP interactions using coarse‐grained models with the Martini force field. Though the model initial ternary complexes (KPI‐E1, KPI‐KPI, KPI‐E2, E1‐E1, E2‐E2, and E1‐E2) generated using HADDOCK (HD) and AlphaFold2 (AF2), the binding free energy profiles and the binding affinities of the domain combinations were investigated via the umbrella sampling with Martini force field. Additionally, membrane‐bound microenvironments at the domain level were modeled. As a result, it was revealed that the KPI domain has a stronger attractive interaction with itself than the E1 and E2 domains, as reported elsewhere. Thus, the KPI domain of APP751 may form additional attractive interactions with E1, E2 and the KPI domain itself, whereas it is absent in APP695. In conclusion, we found that the APP751 homo‐dimer formation is predominant than the homodimerization in APP695, which is facilitated by the presence of the KPI domain.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>36988355</pmid><doi>10.1002/jcc.27100</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0003-1174-4358</orcidid></addata></record> |
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subjects | AlphaFold2 Amyloid beta-Protein Precursor - metabolism amyloid precursor protein Binding Dimerization Dimers Domains Free energy Precursors Protease Protease Inhibitors Protein A Protein Domains Protein Isoforms - metabolism Proteins protein–protein interaction single molecule pull down assay |
title | Characterization of the role of Kunitz‐type protease inhibitor domain in dimerization of amyloid precursor protein |
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