Stochastic Fusion Simulations and Experiments Suggest Passive and Active Roles of Hemagglutinin during Membrane Fusion
Influenza enters the host cell cytoplasm by fusing the viral and host membrane together. Fusion is mediated by hemagglutinin (HA) trimers that undergo conformational change when acidified in the endosome. It is currently debated how many HA trimers, w, and how many conformationally changed HA trimer...
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Veröffentlicht in: | Biophysical journal 2014-02, Vol.106 (4), p.843-854 |
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description | Influenza enters the host cell cytoplasm by fusing the viral and host membrane together. Fusion is mediated by hemagglutinin (HA) trimers that undergo conformational change when acidified in the endosome. It is currently debated how many HA trimers, w, and how many conformationally changed HA trimers, q, are minimally required for fusion. Conclusions vary because there are three common approaches for determining w and q from fusion data. One approach correlates the fusion rate with the fraction of fusogenic HA trimers and leads to the conclusion that one HA trimer is required for fusion. A second approach correlates the fusion rate with the total concentration of fusogenic HA trimers and indicates that more than one HA trimer is required. A third approach applies statistical models to fusion rate data obtained at a single HA density to establish w or q and suggests that more than one HA trimer is required. In this work, all three approaches are investigated through stochastic fusion simulations and experiments to elucidate the roles of HA and its ability to bend the target membrane during fusion. We find that the apparent discrepancies among the results from the various approaches may be resolved if nonfusogenic HA participates in fusion through interactions with a fusogenic HA. Our results, based on H3 and H1 serotypes, suggest that three adjacent HA trimers and one conformationally changed HA trimer are minimally required to induce membrane fusion (w = 3 and q = 1). |
doi_str_mv | 10.1016/j.bpj.2013.12.048 |
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Fusion is mediated by hemagglutinin (HA) trimers that undergo conformational change when acidified in the endosome. It is currently debated how many HA trimers, w, and how many conformationally changed HA trimers, q, are minimally required for fusion. Conclusions vary because there are three common approaches for determining w and q from fusion data. One approach correlates the fusion rate with the fraction of fusogenic HA trimers and leads to the conclusion that one HA trimer is required for fusion. A second approach correlates the fusion rate with the total concentration of fusogenic HA trimers and indicates that more than one HA trimer is required. A third approach applies statistical models to fusion rate data obtained at a single HA density to establish w or q and suggests that more than one HA trimer is required. In this work, all three approaches are investigated through stochastic fusion simulations and experiments to elucidate the roles of HA and its ability to bend the target membrane during fusion. We find that the apparent discrepancies among the results from the various approaches may be resolved if nonfusogenic HA participates in fusion through interactions with a fusogenic HA. Our results, based on H3 and H1 serotypes, suggest that three adjacent HA trimers and one conformationally changed HA trimer are minimally required to induce membrane fusion (w = 3 and q = 1).</description><identifier>ISSN: 0006-3495</identifier><identifier>EISSN: 1542-0086</identifier><identifier>DOI: 10.1016/j.bpj.2013.12.048</identifier><identifier>PMID: 24559987</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Biophysics ; Biopolymers ; Cellular biology ; Correlation ; Cytoplasm ; Density ; Endosomes ; Hemagglutinin Glycoproteins, Influenza Virus - chemistry ; Hemagglutinin Glycoproteins, Influenza Virus - metabolism ; Hydroxyapatite ; Influenza ; Lipid Bilayers - chemistry ; Lipid Bilayers - metabolism ; Membranes ; Models, Biological ; Protein Multimerization ; Stochastic Processes ; Stochasticity ; Trimers ; Virus Internalization</subject><ispartof>Biophysical journal, 2014-02, Vol.106 (4), p.843-854</ispartof><rights>2014 Biophysical Society</rights><rights>Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Biophysical Society Feb 18, 2014</rights><rights>2014 by the Biophysical Society. 2014 Biophysical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c512t-f5f70f0b06da7706939cc304ee9c32292000c02352ac8c6a4924b68d75958b453</citedby><cites>FETCH-LOGICAL-c512t-f5f70f0b06da7706939cc304ee9c32292000c02352ac8c6a4924b68d75958b453</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/PMC3944606/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bpj.2013.12.048$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3550,27924,27925,45995,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24559987$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Donald W.</creatorcontrib><creatorcontrib>Thapar, Vikram</creatorcontrib><creatorcontrib>Clancy, Paulette</creatorcontrib><creatorcontrib>Daniel, Susan</creatorcontrib><title>Stochastic Fusion Simulations and Experiments Suggest Passive and Active Roles of Hemagglutinin during Membrane Fusion</title><title>Biophysical journal</title><addtitle>Biophys J</addtitle><description>Influenza enters the host cell cytoplasm by fusing the viral and host membrane together. Fusion is mediated by hemagglutinin (HA) trimers that undergo conformational change when acidified in the endosome. It is currently debated how many HA trimers, w, and how many conformationally changed HA trimers, q, are minimally required for fusion. Conclusions vary because there are three common approaches for determining w and q from fusion data. One approach correlates the fusion rate with the fraction of fusogenic HA trimers and leads to the conclusion that one HA trimer is required for fusion. A second approach correlates the fusion rate with the total concentration of fusogenic HA trimers and indicates that more than one HA trimer is required. A third approach applies statistical models to fusion rate data obtained at a single HA density to establish w or q and suggests that more than one HA trimer is required. In this work, all three approaches are investigated through stochastic fusion simulations and experiments to elucidate the roles of HA and its ability to bend the target membrane during fusion. We find that the apparent discrepancies among the results from the various approaches may be resolved if nonfusogenic HA participates in fusion through interactions with a fusogenic HA. Our results, based on H3 and H1 serotypes, suggest that three adjacent HA trimers and one conformationally changed HA trimer are minimally required to induce membrane fusion (w = 3 and q = 1).</description><subject>Biophysics</subject><subject>Biopolymers</subject><subject>Cellular biology</subject><subject>Correlation</subject><subject>Cytoplasm</subject><subject>Density</subject><subject>Endosomes</subject><subject>Hemagglutinin Glycoproteins, Influenza Virus - chemistry</subject><subject>Hemagglutinin Glycoproteins, Influenza Virus - metabolism</subject><subject>Hydroxyapatite</subject><subject>Influenza</subject><subject>Lipid Bilayers - chemistry</subject><subject>Lipid Bilayers - metabolism</subject><subject>Membranes</subject><subject>Models, Biological</subject><subject>Protein Multimerization</subject><subject>Stochastic Processes</subject><subject>Stochasticity</subject><subject>Trimers</subject><subject>Virus Internalization</subject><issn>0006-3495</issn><issn>1542-0086</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkl2L1TAQhoMo7tnVH-CNBLzxpnXy1TYIwrLsh7CiePQ6pGnaTWmbY9Ie9N-b7jku6oV4lYF58s68M4PQCwI5AVK86fN61-cUCMsJzYFXj9CGCE4zgKp4jDYAUGSMS3GCTmPsAQgVQJ6iE8qFkLIqN2i_nb2503F2Bl8t0fkJb924DHpOYcR6avDl950NbrTTHPF26TobZ_xJx-j29j5_buY1_OwHG7Fv8Y0dddcNy-wmN-FmCW7q8Ac71kFP9ljkGXrS6iHa58f3DH29uvxycZPdfrx-f3F-mxlB6Jy1oi2hhRqKRpclFJJJYxhwa6VhlEqaHBqgTFBtKlNoLimvi6ophRRVzQU7Q-8OurulHm1jkomgB7VLfnT4obx26s_M5O5U5_eKSc4LKJLA66NA8N-WZF2NLho7DMmLX6IighGgnPLqP1AgFat4uaKv_kJ7v4QpTWKlKHDCyVqbHCgTfIzBtg99E1DrAahepQNQ6wEoQhXcN_Hyd8MPP35tPAFvD4BNY987G1Q0zk7GNi5YM6vGu3_I_wSSn8GF</recordid><startdate>20140218</startdate><enddate>20140218</enddate><creator>Lee, Donald W.</creator><creator>Thapar, Vikram</creator><creator>Clancy, Paulette</creator><creator>Daniel, Susan</creator><general>Elsevier Inc</general><general>Biophysical Society</general><general>The Biophysical Society</general><scope>6I.</scope><scope>AAFTH</scope><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>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>7TB</scope><scope>7U5</scope><scope>L7M</scope><scope>5PM</scope></search><sort><creationdate>20140218</creationdate><title>Stochastic Fusion Simulations and Experiments Suggest Passive and Active Roles of Hemagglutinin during Membrane Fusion</title><author>Lee, Donald W. ; Thapar, Vikram ; Clancy, Paulette ; Daniel, Susan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c512t-f5f70f0b06da7706939cc304ee9c32292000c02352ac8c6a4924b68d75958b453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Biophysics</topic><topic>Biopolymers</topic><topic>Cellular biology</topic><topic>Correlation</topic><topic>Cytoplasm</topic><topic>Density</topic><topic>Endosomes</topic><topic>Hemagglutinin Glycoproteins, Influenza Virus - chemistry</topic><topic>Hemagglutinin Glycoproteins, Influenza Virus - metabolism</topic><topic>Hydroxyapatite</topic><topic>Influenza</topic><topic>Lipid Bilayers - chemistry</topic><topic>Lipid Bilayers - metabolism</topic><topic>Membranes</topic><topic>Models, Biological</topic><topic>Protein Multimerization</topic><topic>Stochastic Processes</topic><topic>Stochasticity</topic><topic>Trimers</topic><topic>Virus Internalization</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Donald W.</creatorcontrib><creatorcontrib>Thapar, Vikram</creatorcontrib><creatorcontrib>Clancy, Paulette</creatorcontrib><creatorcontrib>Daniel, Susan</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biophysical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Donald W.</au><au>Thapar, Vikram</au><au>Clancy, Paulette</au><au>Daniel, Susan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stochastic Fusion Simulations and Experiments Suggest Passive and Active Roles of Hemagglutinin during Membrane Fusion</atitle><jtitle>Biophysical journal</jtitle><addtitle>Biophys J</addtitle><date>2014-02-18</date><risdate>2014</risdate><volume>106</volume><issue>4</issue><spage>843</spage><epage>854</epage><pages>843-854</pages><issn>0006-3495</issn><eissn>1542-0086</eissn><abstract>Influenza enters the host cell cytoplasm by fusing the viral and host membrane together. Fusion is mediated by hemagglutinin (HA) trimers that undergo conformational change when acidified in the endosome. It is currently debated how many HA trimers, w, and how many conformationally changed HA trimers, q, are minimally required for fusion. Conclusions vary because there are three common approaches for determining w and q from fusion data. One approach correlates the fusion rate with the fraction of fusogenic HA trimers and leads to the conclusion that one HA trimer is required for fusion. A second approach correlates the fusion rate with the total concentration of fusogenic HA trimers and indicates that more than one HA trimer is required. A third approach applies statistical models to fusion rate data obtained at a single HA density to establish w or q and suggests that more than one HA trimer is required. In this work, all three approaches are investigated through stochastic fusion simulations and experiments to elucidate the roles of HA and its ability to bend the target membrane during fusion. We find that the apparent discrepancies among the results from the various approaches may be resolved if nonfusogenic HA participates in fusion through interactions with a fusogenic HA. Our results, based on H3 and H1 serotypes, suggest that three adjacent HA trimers and one conformationally changed HA trimer are minimally required to induce membrane fusion (w = 3 and q = 1).</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24559987</pmid><doi>10.1016/j.bpj.2013.12.048</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biophysics Biopolymers Cellular biology Correlation Cytoplasm Density Endosomes Hemagglutinin Glycoproteins, Influenza Virus - chemistry Hemagglutinin Glycoproteins, Influenza Virus - metabolism Hydroxyapatite Influenza Lipid Bilayers - chemistry Lipid Bilayers - metabolism Membranes Models, Biological Protein Multimerization Stochastic Processes Stochasticity Trimers Virus Internalization |
title | Stochastic Fusion Simulations and Experiments Suggest Passive and Active Roles of Hemagglutinin during Membrane Fusion |
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