Structural Determinants for Membrane Association and Dynamic Organization of the Hepatitis C Virus NS3-4A Complex
Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural org...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (38), p.14545-14550 |
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| container_issue | 38 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Brass, Volker Berke, Jan Martin Montserret, Roland Blum, Hubert E. Penin, François Moradpour, Darius |
| description | Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS3-4A are ensured in a cooperative manner by two membrane-binding determinants. We demonstrate that the N-terminal 21 amino acids of NS4A form a transmembrane α-helix that may be involved in intramembrane protein-protein interactions important for the assembly of a functional replication complex. In addition, we demonstrate that amphipathic helix α₀, formed by NS3 residues 12-23, serves as a second essential determinant for membrane association of NS3-4A, allowing proper positioning of the serine protease active site on the membrane. These results allowed us to propose a dynamic model for the membrane association, processing, and structural organization of NS3-4A on the membrane. This model has implications for the functional architecture of the HCV replication complex, proteolytic targeting of host factors, and drug design. |
| doi_str_mv | 10.1073/pnas.0807298105 |
| format | Article |
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It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS3-4A are ensured in a cooperative manner by two membrane-binding determinants. We demonstrate that the N-terminal 21 amino acids of NS4A form a transmembrane α-helix that may be involved in intramembrane protein-protein interactions important for the assembly of a functional replication complex. In addition, we demonstrate that amphipathic helix α₀, formed by NS3 residues 12-23, serves as a second essential determinant for membrane association of NS3-4A, allowing proper positioning of the serine protease active site on the membrane. These results allowed us to propose a dynamic model for the membrane association, processing, and structural organization of NS3-4A on the membrane. This model has implications for the functional architecture of the HCV replication complex, proteolytic targeting of host factors, and drug design.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0807298105</identifier><identifier>PMID: 18799730</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Amino Acid Sequence ; Amino acids ; Antivirals ; Biological Sciences ; Carrier Proteins - chemistry ; Carrier Proteins - genetics ; Carrier Proteins - metabolism ; Crystal structure ; DNA Mutational Analysis ; Hepacivirus ; Hepacivirus - chemistry ; Hepacivirus - enzymology ; Hepacivirus - metabolism ; Hepatitis ; Hepatitis C ; Hepatitis C virus ; Membranes ; Microscopy ; Models, Molecular ; Molecular Sequence Data ; P branes ; Polyproteins ; Proteases ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Proteins ; RNA ; RNA-protein interactions ; Topology ; Viral Matrix Proteins - chemistry ; Viral Matrix Proteins - metabolism ; Viral Nonstructural Proteins - chemistry ; Viral Nonstructural Proteins - metabolism ; Viral Proteins - chemistry ; Viral Proteins - genetics ; Viral Proteins - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-09, Vol.105 (38), p.14545-14550</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Sep 23, 2008</rights><rights>2008 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c596t-375702c85de1cf2c5420e8fa84f8bd5d346182cb49f43335ff60c7306cce9eda3</citedby><cites>FETCH-LOGICAL-c596t-375702c85de1cf2c5420e8fa84f8bd5d346182cb49f43335ff60c7306cce9eda3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/38.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25464266$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25464266$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,725,778,782,801,883,27911,27912,53778,53780,58004,58237</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18799730$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brass, Volker</creatorcontrib><creatorcontrib>Berke, Jan Martin</creatorcontrib><creatorcontrib>Montserret, Roland</creatorcontrib><creatorcontrib>Blum, Hubert E.</creatorcontrib><creatorcontrib>Penin, François</creatorcontrib><creatorcontrib>Moradpour, Darius</creatorcontrib><title>Structural Determinants for Membrane Association and Dynamic Organization of the Hepatitis C Virus NS3-4A Complex</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS3-4A are ensured in a cooperative manner by two membrane-binding determinants. We demonstrate that the N-terminal 21 amino acids of NS4A form a transmembrane α-helix that may be involved in intramembrane protein-protein interactions important for the assembly of a functional replication complex. In addition, we demonstrate that amphipathic helix α₀, formed by NS3 residues 12-23, serves as a second essential determinant for membrane association of NS3-4A, allowing proper positioning of the serine protease active site on the membrane. These results allowed us to propose a dynamic model for the membrane association, processing, and structural organization of NS3-4A on the membrane. This model has implications for the functional architecture of the HCV replication complex, proteolytic targeting of host factors, and drug design.</description><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>Antivirals</subject><subject>Biological Sciences</subject><subject>Carrier Proteins - chemistry</subject><subject>Carrier Proteins - genetics</subject><subject>Carrier Proteins - metabolism</subject><subject>Crystal structure</subject><subject>DNA Mutational Analysis</subject><subject>Hepacivirus</subject><subject>Hepacivirus - chemistry</subject><subject>Hepacivirus - enzymology</subject><subject>Hepacivirus - metabolism</subject><subject>Hepatitis</subject><subject>Hepatitis C</subject><subject>Hepatitis C virus</subject><subject>Membranes</subject><subject>Microscopy</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>P branes</subject><subject>Polyproteins</subject><subject>Proteases</subject><subject>Protein Structure, Secondary</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>RNA</subject><subject>RNA-protein interactions</subject><subject>Topology</subject><subject>Viral Matrix Proteins - chemistry</subject><subject>Viral Matrix Proteins - metabolism</subject><subject>Viral Nonstructural Proteins - chemistry</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Viral Proteins - chemistry</subject><subject>Viral Proteins - genetics</subject><subject>Viral Proteins - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9rFDEYhgdR7Fo9e1KCB8HDtPk9yUVYtmqFag9VryGbSdosM8k0yUjrX2-WXbrqxVMI3_M95M3bNC8RPEGwI6dT0PkECthhKRBkj5oFghK1nEr4uFlAiLtWUEyPmmc5byCEkgn4tDlCopOyI3DR3F6VNJsyJz2AM1tsGn3QoWTgYgJf7LhOOliwzDkar4uPAejQg7P7oEdvwGW61sH_2g2iA-XGgnM71XvxGazAD5_mDL5ekZYuwSqO02DvnjdPnB6yfbE_j5vvHz98W523F5efPq-WF61hkpeWdKyD2AjWW2QcNoxiaIXTgjqx7llPKEcCmzWVjhJCmHMcmhqJG2Ol7TU5bt7vvNO8Hm1vbCg1pJqSH3W6V1F79fck-Bt1HX8qzHiHoayCt3tBirezzUWNPhs7DPVH4pwVhpgQ2HUVfPMPuIlzCjVcZRDhkmNRodMdZFLMOVn38BIE1bZLte1SHbqsG6__DHDg9-VVAOyB7eZBxxQRClFGt453_0GUm4eh2LtS2Vc7dpNLTA8wZpRTzDn5DU_2vis</recordid><startdate>20080923</startdate><enddate>20080923</enddate><creator>Brass, Volker</creator><creator>Berke, Jan Martin</creator><creator>Montserret, Roland</creator><creator>Blum, Hubert E.</creator><creator>Penin, François</creator><creator>Moradpour, Darius</creator><general>National Academy of Sciences</general><general>National Acad 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>7T7</scope><scope>5PM</scope></search><sort><creationdate>20080923</creationdate><title>Structural Determinants for Membrane Association and Dynamic Organization of the Hepatitis C Virus NS3-4A Complex</title><author>Brass, Volker ; 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It is an essential component of the HCV replication complex and a prime target for antiviral intervention. Here, we show that membrane association and structural organization of HCV NS3-4A are ensured in a cooperative manner by two membrane-binding determinants. We demonstrate that the N-terminal 21 amino acids of NS4A form a transmembrane α-helix that may be involved in intramembrane protein-protein interactions important for the assembly of a functional replication complex. In addition, we demonstrate that amphipathic helix α₀, formed by NS3 residues 12-23, serves as a second essential determinant for membrane association of NS3-4A, allowing proper positioning of the serine protease active site on the membrane. These results allowed us to propose a dynamic model for the membrane association, processing, and structural organization of NS3-4A on the membrane. This model has implications for the functional architecture of the HCV replication complex, proteolytic targeting of host factors, and drug design.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>18799730</pmid><doi>10.1073/pnas.0807298105</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Amino acids Antivirals Biological Sciences Carrier Proteins - chemistry Carrier Proteins - genetics Carrier Proteins - metabolism Crystal structure DNA Mutational Analysis Hepacivirus Hepacivirus - chemistry Hepacivirus - enzymology Hepacivirus - metabolism Hepatitis Hepatitis C Hepatitis C virus Membranes Microscopy Models, Molecular Molecular Sequence Data P branes Polyproteins Proteases Protein Structure, Secondary Protein Structure, Tertiary Proteins RNA RNA-protein interactions Topology Viral Matrix Proteins - chemistry Viral Matrix Proteins - metabolism Viral Nonstructural Proteins - chemistry Viral Nonstructural Proteins - metabolism Viral Proteins - chemistry Viral Proteins - genetics Viral Proteins - metabolism |
| title | Structural Determinants for Membrane Association and Dynamic Organization of the Hepatitis C Virus NS3-4A Complex |
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