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dc.contributor.authorMishra, Ashwini K.
dc.contributor.authorGangwani, Laxman
dc.contributor.authorDavis, Roger J.
dc.contributor.authorLambright, David G.
dc.date2022-08-11T08:09:33.000
dc.date.accessioned2022-08-23T16:35:06Z
dc.date.available2022-08-23T16:35:06Z
dc.date.issued2007-08-28
dc.date.submitted2009-03-16
dc.identifier.citationProc Natl Acad Sci U S A. 2007 Aug 28;104(35):13930-5. Epub 2007 Aug 17. <a href="http://dx.doi.org/10.1073/pnas.0704915104">Link to article on publisher's site</a>
dc.identifier.issn0027-8424 (Print)
dc.identifier.doi10.1073/pnas.0704915104
dc.identifier.pmid17704259
dc.identifier.urihttp://hdl.handle.net/20.500.14038/38483
dc.description.abstractEukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded beta helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis. However, ZPR1 efficiently displaces the exchange factor eEF1Balpha from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17704259&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1073/pnas.0704915104
dc.rights<p>Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.</p>
dc.subjectgrowth factor receptor
dc.subjectstructure
dc.subjectneurodegeneration
dc.subjectspinal muscular atrophy
dc.subjectcell cycle
dc.subjectBiochemistry
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectMolecular Biology
dc.subjectStructural Biology
dc.titleStructural insights into the interaction of the evolutionarily conserved ZPR1 domain tandem with eukaryotic EF1A, receptors, and SMN complexes
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume104
dc.source.issue35
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2355&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/1356
dc.identifier.contextkey783038
refterms.dateFOA2022-08-23T16:35:06Z
html.description.abstract<p>Eukaryotic genomes encode a zinc finger protein (ZPR1) with tandem ZPR1 domains. In response to growth stimuli, ZPR1 assembles into complexes with eukaryotic translation elongation factor 1A (eEF1A) and the survival motor neurons protein. To gain insight into the structural mechanisms underlying the essential function of ZPR1 in diverse organisms, we determined the crystal structure of a ZPR1 domain tandem and characterized the interaction with eEF1A. The ZPR1 domain consists of an elongation initiation factor 2-like zinc finger and a double-stranded beta helix with a helical hairpin insertion. ZPR1 binds preferentially to GDP-bound eEF1A but does not directly influence the kinetics of nucleotide exchange or GTP hydrolysis. However, ZPR1 efficiently displaces the exchange factor eEF1Balpha from preformed nucleotide-free complexes, suggesting that it may function as a negative regulator of eEF1A activation. Structure-based mutational and complementation analyses reveal a conserved binding epitope for eEF1A that is required for normal cell growth, proliferation, and cell cycle progression. Structural differences between the ZPR1 domains contribute to the observed functional divergence and provide evidence for distinct modalities of interaction with eEF1A and survival motor neuron complexes.</p>
dc.identifier.submissionpathoapubs/1356
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages13930-5


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