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dc.contributor.authorTamir, Sagi
Rotem-Bamberger, Shahar
Katz, Chen
Morcos, Faruck
Hailey, Kendra L.
Zuris, John A.
Wang, Charles
Conlan, Andrea R.
Lipper, Colin H.
Paddock, Mark L.
Mittler, Ron
Onuchic, José N.
Jennings, Patricia A.
Friedler, Assaf
Nechushtai, Rachel
dc.date.accessioned 2014-04-14T20:56:35Z
dc.date.available 2014-04-14T20:56:35Z
dc.date.issued 2014
dc.identifier.citation Tamir, Sagi, Rotem-Bamberger, Shahar, Katz, Chen, et al.. "Integrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1." PNAS Early Edition, (2014) PNAS: http://dx.doi.org/10.1073/pnas.1403770111.
dc.identifier.urihttps://hdl.handle.net/1911/75892
dc.description.abstract Life 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.
dc.language.iso eng
dc.publisher PNAS
dc.rights Article 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.
dc.title Integrated strategy reveals the protein interface between cancer targets Bcl-2 and NAF-1
dc.type Journal article
dc.contributor.funder National Institutes of Health
dc.contributor.funder Cancer Prevention and Research Institute of Texas
dc.contributor.funder National Science Foundation
dc.citation.journalTitle PNAS Early Edition
dc.contributor.org Center for Theoretical Biological Physics
dc.subject.keywordCisd1
Cisd2
mitoNEET
Miner1
CDGSH
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.1403770111
dc.identifier.pmcid PMC3986192
dc.identifier.pmid 24706857
dc.identifier.grantID GM54038 (National Institutes of Health)
dc.identifier.grantID GM101467 (National Institutes of Health)
dc.identifier.grantID PHY-1308264 (National Science Foundation)
dc.identifier.grantID MCB-1214457 (National Science Foundation)
dc.type.publication publisher version


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