The Molecular Basis for Perform Oligomerization and Transmembrane Pore Assembly

Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. D...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Immunity (Cambridge, Mass.) Mass.), 2009-05, Vol.30 (5), p.684-695
Hauptverfasser: Baran, K, Dunstone, M, Chia, J, Ciccone, A, Browne, KA, Clarke, CJP, Lukoyanova, N, Saibil, H, Whisstock, J C, Voskoboinik, I, Trapani, JA
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 695
container_issue 5
container_start_page 684
container_title Immunity (Cambridge, Mass.)
container_volume 30
creator Baran, K
Dunstone, M
Chia, J
Ciccone, A
Browne, KA
Clarke, CJP
Lukoyanova, N
Saibil, H
Whisstock, J C
Voskoboinik, I
Trapani, JA
description Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the opposing charges on residues Arg213 (positive) and Glu343 (negative) to be critical for intermolecular interaction. Specifically, disrupting this interaction had no effect on perforin synthesis, folding, or trafficking in the killer cell, but caused a marked kinetic defect of oligomerization at the target cell membrane, severely disrupting lysis and granzyme B-induced apoptosis. Our study provides important insights into perforin's mechanism of action.
doi_str_mv 10.1016/j.immuni.2009.03.016
format Article
fullrecord <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_miscellaneous_815543410</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>815543410</sourcerecordid><originalsourceid>FETCH-proquest_miscellaneous_8155434103</originalsourceid><addsrcrecordid>eNqNy70SATEUBeAUzPh9A8XtVOLG_qDEMBpDsb0J7hKTbMi1BU8vhQdQfXPOnCPEQKFUqPLxXRrn6srICeJcYiJj2RBthdN0NM1V0hId5juiSrM5tsW-uBHsvKVzbXWApWbDUPoABwoRB3trrt5RMB_9Mr4CXV2gCLpiR-4UJTj4QLBgjtm-e6JZasvU_9kVw826WG1Hj-CfNfHr6Ayfydr49DUfZyrL0iRVmPy__AL7tUjT</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>815543410</pqid></control><display><type>article</type><title>The Molecular Basis for Perform Oligomerization and Transmembrane Pore Assembly</title><source>Cell Press Free Archives</source><source>Access via ScienceDirect (Elsevier)</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Baran, K ; Dunstone, M ; Chia, J ; Ciccone, A ; Browne, KA ; Clarke, CJP ; Lukoyanova, N ; Saibil, H ; Whisstock, J C ; Voskoboinik, I ; Trapani, JA</creator><creatorcontrib>Baran, K ; Dunstone, M ; Chia, J ; Ciccone, A ; Browne, KA ; Clarke, CJP ; Lukoyanova, N ; Saibil, H ; Whisstock, J C ; Voskoboinik, I ; Trapani, JA</creatorcontrib><description>Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the opposing charges on residues Arg213 (positive) and Glu343 (negative) to be critical for intermolecular interaction. Specifically, disrupting this interaction had no effect on perforin synthesis, folding, or trafficking in the killer cell, but caused a marked kinetic defect of oligomerization at the target cell membrane, severely disrupting lysis and granzyme B-induced apoptosis. Our study provides important insights into perforin's mechanism of action.</description><identifier>ISSN: 1074-7613</identifier><identifier>DOI: 10.1016/j.immuni.2009.03.016</identifier><language>eng</language><subject>Apoptosis</subject><ispartof>Immunity (Cambridge, Mass.), 2009-05, Vol.30 (5), p.684-695</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Baran, K</creatorcontrib><creatorcontrib>Dunstone, M</creatorcontrib><creatorcontrib>Chia, J</creatorcontrib><creatorcontrib>Ciccone, A</creatorcontrib><creatorcontrib>Browne, KA</creatorcontrib><creatorcontrib>Clarke, CJP</creatorcontrib><creatorcontrib>Lukoyanova, N</creatorcontrib><creatorcontrib>Saibil, H</creatorcontrib><creatorcontrib>Whisstock, J C</creatorcontrib><creatorcontrib>Voskoboinik, I</creatorcontrib><creatorcontrib>Trapani, JA</creatorcontrib><title>The Molecular Basis for Perform Oligomerization and Transmembrane Pore Assembly</title><title>Immunity (Cambridge, Mass.)</title><description>Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the opposing charges on residues Arg213 (positive) and Glu343 (negative) to be critical for intermolecular interaction. Specifically, disrupting this interaction had no effect on perforin synthesis, folding, or trafficking in the killer cell, but caused a marked kinetic defect of oligomerization at the target cell membrane, severely disrupting lysis and granzyme B-induced apoptosis. Our study provides important insights into perforin's mechanism of action.</description><subject>Apoptosis</subject><issn>1074-7613</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNqNy70SATEUBeAUzPh9A8XtVOLG_qDEMBpDsb0J7hKTbMi1BU8vhQdQfXPOnCPEQKFUqPLxXRrn6srICeJcYiJj2RBthdN0NM1V0hId5juiSrM5tsW-uBHsvKVzbXWApWbDUPoABwoRB3trrt5RMB_9Mr4CXV2gCLpiR-4UJTj4QLBgjtm-e6JZasvU_9kVw826WG1Hj-CfNfHr6Ayfydr49DUfZyrL0iRVmPy__AL7tUjT</recordid><startdate>20090501</startdate><enddate>20090501</enddate><creator>Baran, K</creator><creator>Dunstone, M</creator><creator>Chia, J</creator><creator>Ciccone, A</creator><creator>Browne, KA</creator><creator>Clarke, CJP</creator><creator>Lukoyanova, N</creator><creator>Saibil, H</creator><creator>Whisstock, J C</creator><creator>Voskoboinik, I</creator><creator>Trapani, JA</creator><scope>7T5</scope><scope>H94</scope></search><sort><creationdate>20090501</creationdate><title>The Molecular Basis for Perform Oligomerization and Transmembrane Pore Assembly</title><author>Baran, K ; Dunstone, M ; Chia, J ; Ciccone, A ; Browne, KA ; Clarke, CJP ; Lukoyanova, N ; Saibil, H ; Whisstock, J C ; Voskoboinik, I ; Trapani, JA</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_miscellaneous_8155434103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Apoptosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Baran, K</creatorcontrib><creatorcontrib>Dunstone, M</creatorcontrib><creatorcontrib>Chia, J</creatorcontrib><creatorcontrib>Ciccone, A</creatorcontrib><creatorcontrib>Browne, KA</creatorcontrib><creatorcontrib>Clarke, CJP</creatorcontrib><creatorcontrib>Lukoyanova, N</creatorcontrib><creatorcontrib>Saibil, H</creatorcontrib><creatorcontrib>Whisstock, J C</creatorcontrib><creatorcontrib>Voskoboinik, I</creatorcontrib><creatorcontrib>Trapani, JA</creatorcontrib><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Immunity (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Baran, K</au><au>Dunstone, M</au><au>Chia, J</au><au>Ciccone, A</au><au>Browne, KA</au><au>Clarke, CJP</au><au>Lukoyanova, N</au><au>Saibil, H</au><au>Whisstock, J C</au><au>Voskoboinik, I</au><au>Trapani, JA</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Molecular Basis for Perform Oligomerization and Transmembrane Pore Assembly</atitle><jtitle>Immunity (Cambridge, Mass.)</jtitle><date>2009-05-01</date><risdate>2009</risdate><volume>30</volume><issue>5</issue><spage>684</spage><epage>695</epage><pages>684-695</pages><issn>1074-7613</issn><abstract>Perforin, a pore-forming protein secreted by cytotoxic lymphocytes, is indispensable for destroying virus-infected cells and for maintaining immune homeostasis. Perforin polymerizes into transmembrane channels that inflict osmotic stress and facilitate target cell uptake of proapoptotic granzymes. Despite this, the mechanism through which perforin monomers self-associate remains unknown. Our current study establishes the molecular basis for perforin oligomerization and pore assembly. We show that after calcium-dependent membrane binding, direct ionic attraction between the opposite faces of adjacent perforin monomers was necessary for pore formation. By using mutagenesis, we identified the opposing charges on residues Arg213 (positive) and Glu343 (negative) to be critical for intermolecular interaction. Specifically, disrupting this interaction had no effect on perforin synthesis, folding, or trafficking in the killer cell, but caused a marked kinetic defect of oligomerization at the target cell membrane, severely disrupting lysis and granzyme B-induced apoptosis. Our study provides important insights into perforin's mechanism of action.</abstract><doi>10.1016/j.immuni.2009.03.016</doi></addata></record>
fulltext fulltext
identifier ISSN: 1074-7613
ispartof Immunity (Cambridge, Mass.), 2009-05, Vol.30 (5), p.684-695
issn 1074-7613
language eng
recordid cdi_proquest_miscellaneous_815543410
source Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals
subjects Apoptosis
title The Molecular Basis for Perform Oligomerization and Transmembrane Pore Assembly
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T14%3A45%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20Molecular%20Basis%20for%20Perform%20Oligomerization%20and%20Transmembrane%20Pore%20Assembly&rft.jtitle=Immunity%20(Cambridge,%20Mass.)&rft.au=Baran,%20K&rft.date=2009-05-01&rft.volume=30&rft.issue=5&rft.spage=684&rft.epage=695&rft.pages=684-695&rft.issn=1074-7613&rft_id=info:doi/10.1016/j.immuni.2009.03.016&rft_dat=%3Cproquest%3E815543410%3C/proquest%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=815543410&rft_id=info:pmid/&rfr_iscdi=true