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Structural Basis of BFL-1 for Its Interaction with BAX and Its Anti-apoptotic Action in Mammalian and Yeast Cells
BFL-1 is the smallest member of the BCL-2 family and has been shown to retard apoptosis in various cell lines. However, the structural basis for its function remains unclear. Molecular modeling showed that BFL-1 could have a similar core structure as BCL-xL, consisting of seven α helices, although b...
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Published in: | The Journal of biological chemistry 2000-04, Vol.275 (15), p.11092-11099 |
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description | BFL-1 is the smallest member of the BCL-2 family and has been shown to retard apoptosis in various cell lines. However, the structural basis for its function remains unclear. Molecular modeling showed that BFL-1 could have a similar core structure as BCL-xL, consisting of seven α helices, although both proteins share only the conserved BCL-2 homology domains (BH1 and BH2 domains), but otherwise have very limited sequence homology, particularly in the N-terminal region. We demonstrated in the yeast two-hybrid system that BFL-1 interacts strongly with human BAX but is not able to form homodimers nor to interact with human BCL-2 or BCL-xL. Overexpression experiments in REF52 rat fibroblasts showed that BFL-1 conferred increased resistance to apoptosis induced by serum deprivation. BFL-1 had also the ability to neutralize BAX lethality in yeast. BAX requires the BH3 domain for interaction with BFL-1. However, the minimal region of BFL-1 for the interaction with BAX in coimmunoprecipitation experiments was not sufficient to protect cells from apoptosis. Further examination of BFL-1 and several other anti-apoptotic proteins suggests a more general type of structure based on structural motifs,i.e. a hydrophobic pocket for the binding of proapoptotic proteins, rather than extended sequence homologies. |
doi_str_mv | 10.1074/jbc.275.15.11092 |
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However, the structural basis for its function remains unclear. Molecular modeling showed that BFL-1 could have a similar core structure as BCL-xL, consisting of seven α helices, although both proteins share only the conserved BCL-2 homology domains (BH1 and BH2 domains), but otherwise have very limited sequence homology, particularly in the N-terminal region. We demonstrated in the yeast two-hybrid system that BFL-1 interacts strongly with human BAX but is not able to form homodimers nor to interact with human BCL-2 or BCL-xL. Overexpression experiments in REF52 rat fibroblasts showed that BFL-1 conferred increased resistance to apoptosis induced by serum deprivation. BFL-1 had also the ability to neutralize BAX lethality in yeast. BAX requires the BH3 domain for interaction with BFL-1. However, the minimal region of BFL-1 for the interaction with BAX in coimmunoprecipitation experiments was not sufficient to protect cells from apoptosis. Further examination of BFL-1 and several other anti-apoptotic proteins suggests a more general type of structure based on structural motifs,i.e. a hydrophobic pocket for the binding of proapoptotic proteins, rather than extended sequence homologies.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.275.15.11092</identifier><identifier>PMID: 10753914</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Animals ; Apoptosis ; Base Sequence ; bcl-2-Associated X Protein ; Binding Sites ; Cell Death ; Cell Line ; Humans ; Minor Histocompatibility Antigens ; Models, Molecular ; Molecular Sequence Data ; Proteins - chemistry ; Proteins - physiology ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-bcl-2 ; Rats ; Saccharomyces cerevisiae - physiology</subject><ispartof>The Journal of biological chemistry, 2000-04, Vol.275 (15), p.11092-11099</ispartof><rights>2000 © 2000 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-851e60fc420cb7b0326c831700a7f3b96b6712788b0204c8ac7ab7ba710093e13</citedby><cites>FETCH-LOGICAL-c417t-851e60fc420cb7b0326c831700a7f3b96b6712788b0204c8ac7ab7ba710093e13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0021925819809535$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3536,27900,27901,45755</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10753914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Cowan-Jacob, Sandra W.</creatorcontrib><creatorcontrib>Simonen, Marjo</creatorcontrib><creatorcontrib>Greenhalf, William</creatorcontrib><creatorcontrib>Heim, Jutta</creatorcontrib><creatorcontrib>Meyhack, Bernd</creatorcontrib><title>Structural Basis of BFL-1 for Its Interaction with BAX and Its Anti-apoptotic Action in Mammalian and Yeast Cells</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>BFL-1 is the smallest member of the BCL-2 family and has been shown to retard apoptosis in various cell lines. However, the structural basis for its function remains unclear. Molecular modeling showed that BFL-1 could have a similar core structure as BCL-xL, consisting of seven α helices, although both proteins share only the conserved BCL-2 homology domains (BH1 and BH2 domains), but otherwise have very limited sequence homology, particularly in the N-terminal region. We demonstrated in the yeast two-hybrid system that BFL-1 interacts strongly with human BAX but is not able to form homodimers nor to interact with human BCL-2 or BCL-xL. Overexpression experiments in REF52 rat fibroblasts showed that BFL-1 conferred increased resistance to apoptosis induced by serum deprivation. BFL-1 had also the ability to neutralize BAX lethality in yeast. BAX requires the BH3 domain for interaction with BFL-1. However, the minimal region of BFL-1 for the interaction with BAX in coimmunoprecipitation experiments was not sufficient to protect cells from apoptosis. Further examination of BFL-1 and several other anti-apoptotic proteins suggests a more general type of structure based on structural motifs,i.e. a hydrophobic pocket for the binding of proapoptotic proteins, rather than extended sequence homologies.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Base Sequence</subject><subject>bcl-2-Associated X Protein</subject><subject>Binding Sites</subject><subject>Cell Death</subject><subject>Cell Line</subject><subject>Humans</subject><subject>Minor Histocompatibility Antigens</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Proteins - chemistry</subject><subject>Proteins - physiology</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2</subject><subject>Rats</subject><subject>Saccharomyces cerevisiae - physiology</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><recordid>eNp1kE1LAzEQhoMoWqt3T5KDeNs6sx_Nrre2-FGoeFBBTyGbZm1kd1OTrOK_N3V7EMEwkMM878vwEHKCMEJg6cVbKUcxy0YYBqGId8gAIU-iJMPnXTIAiDEq4iw_IIfOvUF4aYH75CCEs6TAdEDeH7ztpO-sqOlUOO2oqej0ehEhrYylc-_ovPXKCum1aemn9is6nTxT0S5_lpPW60iszdobryWd9Jhu6Z1oGlFr0f6gL0o4T2eqrt0R2atE7dTx9h-Sp-urx9lttLi_mc8mi0imyHyUZ6jGUMk0BlmyEpJ4LPMEGYBgVVIW43LMMGZ5XkIMqcyFZCJwgiFAkShMhuS8711b894p53mjnQwXiFaZzvEAIktxA0IPSmucs6ria6sbYb84At9o5kEzD5o5htloDpHTbXdXNmr5K9B7DcBZD6z06-pTW8VLbeRKNX97LntMBREfWlnupFatVMsQkZ4vjf7_iG80e5YR</recordid><startdate>20000414</startdate><enddate>20000414</enddate><creator>Zhang, Hong</creator><creator>Cowan-Jacob, Sandra W.</creator><creator>Simonen, Marjo</creator><creator>Greenhalf, William</creator><creator>Heim, Jutta</creator><creator>Meyhack, Bernd</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</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>7X8</scope></search><sort><creationdate>20000414</creationdate><title>Structural Basis of BFL-1 for Its Interaction with BAX and Its Anti-apoptotic Action in Mammalian and Yeast Cells</title><author>Zhang, Hong ; Cowan-Jacob, Sandra W. ; Simonen, Marjo ; Greenhalf, William ; Heim, Jutta ; Meyhack, Bernd</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-851e60fc420cb7b0326c831700a7f3b96b6712788b0204c8ac7ab7ba710093e13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Base Sequence</topic><topic>bcl-2-Associated X Protein</topic><topic>Binding Sites</topic><topic>Cell Death</topic><topic>Cell Line</topic><topic>Humans</topic><topic>Minor Histocompatibility Antigens</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Proteins - chemistry</topic><topic>Proteins - physiology</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-bcl-2</topic><topic>Rats</topic><topic>Saccharomyces cerevisiae - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Cowan-Jacob, Sandra W.</creatorcontrib><creatorcontrib>Simonen, Marjo</creatorcontrib><creatorcontrib>Greenhalf, William</creatorcontrib><creatorcontrib>Heim, Jutta</creatorcontrib><creatorcontrib>Meyhack, Bernd</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>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Hong</au><au>Cowan-Jacob, Sandra W.</au><au>Simonen, Marjo</au><au>Greenhalf, William</au><au>Heim, Jutta</au><au>Meyhack, Bernd</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural Basis of BFL-1 for Its Interaction with BAX and Its Anti-apoptotic Action in Mammalian and Yeast Cells</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2000-04-14</date><risdate>2000</risdate><volume>275</volume><issue>15</issue><spage>11092</spage><epage>11099</epage><pages>11092-11099</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>BFL-1 is the smallest member of the BCL-2 family and has been shown to retard apoptosis in various cell lines. 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subjects | Amino Acid Sequence Animals Apoptosis Base Sequence bcl-2-Associated X Protein Binding Sites Cell Death Cell Line Humans Minor Histocompatibility Antigens Models, Molecular Molecular Sequence Data Proteins - chemistry Proteins - physiology Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-bcl-2 Rats Saccharomyces cerevisiae - physiology |
title | Structural Basis of BFL-1 for Its Interaction with BAX and Its Anti-apoptotic Action in Mammalian and Yeast Cells |
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