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Article: The structural and biological significance of the EAAEAE insert in the α-domain of human neuronal growth inhibitory factor

TitleThe structural and biological significance of the EAAEAE insert in the α-domain of human neuronal growth inhibitory factor
Authors
Issue Date2009
PublisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.febsjournal.org/
Citation
FEBS Journal, 2009, v. 276 n. 13, p. 3547-3558 How to Cite?
AbstractHuman neuronal growth inhibitory factor (hGIF) is able to inhibit the outgrowth of neurons. As compared with the amino acid sequences of metallothionein 1/2, hGIF contains two insertions: a Thr at position 5 and an acidic hexapeptide EAAEAE(55-60) close to the C-terminus. Moreover, all mammalian growth inhibitory factor sequences contain a conserved CPCP(6-9) motif. Previous studies have demonstrated that the TCPCP(5-9) motif is pivotal to its bioactivity, but no specific role has been assigned to the unique EAAEAE(55-60) insert. To investigate the potential structural and biological significance of the EAAEAE(55-60) insert, several mutants were constructed and investigated in detail. Notably, deletion of the acidic insert (the Δ55-60 mutant) reduced the inhibitory activity, whereas the bioactivities of other mutants did not change much. Then, spectroscopic characterization and molecular dynamics simulation were performed to investigate the potential causes of the reduced bioactivity of the Δ55-60 mutant. It was found that the domain-domain interaction mechanism of hGIF was different from that of metallothionein 2. It was also shown that the acidic insert could regulate the interdomain interactions in hGIF, leading to the structural change in the β-domain, which resulted in the alteration of the solvent accessibility and metal release ability, thus playing an important role in the biological activity of hGIF. Our studies provided useful information on the domain-domain interaction at the molecular level for the first time, and shed new light on the mechanism of the bioactivity of hGIF. © 2009 FEBS.
Persistent Identifierhttp://hdl.handle.net/10722/168388
ISSN
2015 Impact Factor: 4.237
2015 SCImago Journal Rankings: 2.141
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCai, Ben_US
dc.contributor.authorDing, ZCen_US
dc.contributor.authorZhang, Qen_US
dc.contributor.authorNi, FYen_US
dc.contributor.authorWang, Hen_US
dc.contributor.authorZheng, Qen_US
dc.contributor.authorWang, Yen_US
dc.contributor.authorZhou, GMen_US
dc.contributor.authorWang, KQen_US
dc.contributor.authorSun, HZen_US
dc.contributor.authorWu, HMen_US
dc.contributor.authorHuang, ZXen_US
dc.date.accessioned2012-10-08T03:18:18Z-
dc.date.available2012-10-08T03:18:18Z-
dc.date.issued2009en_US
dc.identifier.citationFEBS Journal, 2009, v. 276 n. 13, p. 3547-3558en_US
dc.identifier.issn1742-464Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/168388-
dc.description.abstractHuman neuronal growth inhibitory factor (hGIF) is able to inhibit the outgrowth of neurons. As compared with the amino acid sequences of metallothionein 1/2, hGIF contains two insertions: a Thr at position 5 and an acidic hexapeptide EAAEAE(55-60) close to the C-terminus. Moreover, all mammalian growth inhibitory factor sequences contain a conserved CPCP(6-9) motif. Previous studies have demonstrated that the TCPCP(5-9) motif is pivotal to its bioactivity, but no specific role has been assigned to the unique EAAEAE(55-60) insert. To investigate the potential structural and biological significance of the EAAEAE(55-60) insert, several mutants were constructed and investigated in detail. Notably, deletion of the acidic insert (the Δ55-60 mutant) reduced the inhibitory activity, whereas the bioactivities of other mutants did not change much. Then, spectroscopic characterization and molecular dynamics simulation were performed to investigate the potential causes of the reduced bioactivity of the Δ55-60 mutant. It was found that the domain-domain interaction mechanism of hGIF was different from that of metallothionein 2. It was also shown that the acidic insert could regulate the interdomain interactions in hGIF, leading to the structural change in the β-domain, which resulted in the alteration of the solvent accessibility and metal release ability, thus playing an important role in the biological activity of hGIF. Our studies provided useful information on the domain-domain interaction at the molecular level for the first time, and shed new light on the mechanism of the bioactivity of hGIF. © 2009 FEBS.en_US
dc.languageengen_US
dc.publisherWiley-Blackwell Publishing Ltd.. The Journal's web site is located at http://www.febsjournal.org/en_US
dc.relation.ispartofFEBS Journalen_US
dc.subject.meshAmino Acid Sequence - Geneticsen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCells, Cultureden_US
dc.subject.meshConserved Sequence - Geneticsen_US
dc.subject.meshHumansen_US
dc.subject.meshHydrogen-Ion Concentrationen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshNerve Tissue Proteins - Chemistry - Genetics - Metabolismen_US
dc.subject.meshNeurons - Cytology - Metabolismen_US
dc.subject.meshNuclear Magnetic Resonance, Biomolecularen_US
dc.subject.meshProtein Conformationen_US
dc.subject.meshProtein Denaturationen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Wistaren_US
dc.subject.meshZinc - Metabolismen_US
dc.titleThe structural and biological significance of the EAAEAE insert in the α-domain of human neuronal growth inhibitory factoren_US
dc.typeArticleen_US
dc.identifier.emailSun, HZ:hsun@hkucc.hku.hken_US
dc.identifier.authoritySun, HZ=rp00777en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1111/j.1742-4658.2009.07075.xen_US
dc.identifier.pmid19490120-
dc.identifier.scopuseid_2-s2.0-67650498372en_US
dc.identifier.hkuros158585-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67650498372&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume276en_US
dc.identifier.issue13en_US
dc.identifier.spage3547en_US
dc.identifier.epage3558en_US
dc.identifier.isiWOS:000266922900011-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridCai, B=36484162900en_US
dc.identifier.scopusauthoridDing, ZC=14424225400en_US
dc.identifier.scopusauthoridZhang, Q=35515964300en_US
dc.identifier.scopusauthoridNi, FY=9841840800en_US
dc.identifier.scopusauthoridWang, H=15052706700en_US
dc.identifier.scopusauthoridZheng, Q=36887872800en_US
dc.identifier.scopusauthoridWang, Y=36078812500en_US
dc.identifier.scopusauthoridZhou, GM=8449295200en_US
dc.identifier.scopusauthoridWang, KQ=7501398928en_US
dc.identifier.scopusauthoridSun, HZ=7404827446en_US
dc.identifier.scopusauthoridWu, HM=13808047800en_US
dc.identifier.scopusauthoridHuang, ZX=7406221847en_US
dc.identifier.citeulike4928863-

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