Integrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1

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dc.citation.journalTitlePNAS Early Editionen_US
dc.contributor.authorTamir, Sagien_US
dc.contributor.authorRotem-Bamberger, Shaharen_US
dc.contributor.authorKatz, Chenen_US
dc.contributor.authorMorcos, Farucken_US
dc.contributor.authorHailey, Kendra L.en_US
dc.contributor.authorZuris, John A.en_US
dc.contributor.authorWang, Charlesen_US
dc.contributor.authorConlan, Andrea R.en_US
dc.contributor.authorLipper, Colin H.en_US
dc.contributor.authorPaddock, Mark L.en_US
dc.contributor.authorMittler, Ronen_US
dc.contributor.authorOnuchic, José Nelsonen_US
dc.contributor.authorJennings, Patricia A.en_US
dc.contributor.authorFriedler, Assafen_US
dc.contributor.authorNechushtai, Rachelen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2014-04-14T20:56:35Zen_US
dc.date.available2014-04-14T20:56:35Zen_US
dc.date.issued2014en_US
dc.description.abstractLife requires orchestrated control of cell proliferation, cell maintenance, and cell death. Involved in these decisions are protein complexes that assimilate a variety of inputs that report on the status of the cell and lead to an output response. Among the proteins involved in this response are nutrient-deprivation autophagy factor-1 (NAF-1)- and Bcl-2. NAF-1 is a homodimeric member of the novel Fe-S protein NEET family, which binds two 2Fe-2S clusters. NAF-1 is an important partner for Bcl-2 at the endoplasmic reticulum to functionally antagonize Beclin 1-dependent autophagy [Chang NC, Nguyen M, Germain M, Shore GC (2010) EMBO J 29 (3):606–618]. We used an integrated approach involving peptide array, deuterium exchange mass spectrometry (DXMS), and functional studies aided by the power of sufficient constraints from direct coupling analysis (DCA) to determine the dominant docked conformation of the NAF-1–Bcl-2 complex. NAF-1 binds to both the pro- and antiapoptotic regions (BH3 and BH4) of Bcl-2, as demonstrated by a nested protein fragment analysis in a peptide array and DXMS analysis. A combination of the solution studies together with a new application of DCA to the eukaryotic proteins NAF-1 and Bcl-2 provided sufficient constraints at amino acid resolution to predict the interaction surfaces and orientation of the protein–protein interactions involved in the docked structure. The specific integrated approach described in this paper provides the first structural information, to our knowledge, for future targeting of the NAF-1–Bcl-2 complex in the regulation of apoptosis/autophagy in cancer biology.en_US
dc.identifier.citationTamir, Sagi, Rotem-Bamberger, Shahar, Katz, Chen, et al.. "Integrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1." <i>PNAS Early Edition,</i> (2014) PNAS: http://dx.doi.org/10.1073/pnas.1403770111.en_US
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.1403770111en_US
dc.identifier.urihttps://hdl.handle.net/1911/75892en_US
dc.language.isoengen_US
dc.publisherPNASen_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.subject.keywordCisd1en_US
dc.subject.keywordCisd2en_US
dc.subject.keywordmitoNEETen_US
dc.subject.keywordMiner1en_US
dc.subject.keywordCDGSHen_US
dc.titleIntegrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1en_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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