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Article: Backbone dynamics measurements on leukemia inhibitory factor, a rigid four-helical bundle cytokine

TitleBackbone dynamics measurements on leukemia inhibitory factor, a rigid four-helical bundle cytokine
Authors
KeywordsAmide exchange
Cytokine
Leukemia inhibitory factor
15N relaxation
NMR
Issue Date2000
PublisherCold Spring Harbor Laboratory Press, Publications Department. The Journal's web site is located at http://www.proteinscience.org/
Citation
Protein Science, 2000, v. 9 n. 4, p. 671-682 How to Cite?
AbstractThe backbone dynamics of the four-helical bundle cytokine leukemia inhibitory factor (LIF) have been investigated using 15N NMR relaxation and amide proton exchange measurements on a murine-human chimera, MH35-LIF. For rapid backbone motions (on a time scale of 10 ps to 100 ns), as probed by 15N relaxation measurements, the dynamics parameters were calculated using the model-free formalism incorporating the model selection approach. The principal components of the inertia tensor of MH35-LIF, as calculated from its NMR structure, were 1:0.98:0.38. The global rotational motion of the molecule was, therefore, assumed to be axially symmetric in the analysis of its relaxation data. This yielded a diffusion anisotropy D(parallel)/D(perpendicular) of 1.31 and an effective correlation time (4D(perpendicular) + 2D(parallel))(-1) of 8.9 ns. The average values of the order parameters (S2) for the four helices, the long interhelical loops, and the N-terminus were 0.91, 0.84, and 0.65, respectively, indicating that LIF is fairly rigid in solution, except at the N-terminus. The S2 values for the long interhelical loops of MH35-LIF were higher than those of their counterparts in short-chain members of the four-helical bundle cytokine family. Residues involved in LIF receptor binding showed no consistent pattern of backbone mobilities, with S2 values ranging from 0.71 to 0.95, but residues contributing to receptor binding site III had relatively lower S2 values, implying higher amplitude motions than for the backbone of sites I and II. In the relatively slow motion regime, backbone amide exchange measurements showed that a number of amides from the helical bundle exchanged extremely slowly, persisting for several months in 2H2O at 37 degrees C. Evidence for local unfolding was considered, and correlations among various structure-related parameters and the backbone amide exchange rates were examined. Both sets of data concur in showing that LIF is one of the most rigid four-helical bundle cytokines.
Persistent Identifierhttp://hdl.handle.net/10722/48976
ISSN
2015 Impact Factor: 3.039
2015 SCImago Journal Rankings: 2.029
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYao, Sen_HK
dc.contributor.authorSmith, DKen_HK
dc.contributor.authorHinds, MGen_HK
dc.contributor.authorZhang, JGen_HK
dc.contributor.authorNicola, NAen_HK
dc.contributor.authorNorton, RSen_HK
dc.date.accessioned2008-06-12T06:31:12Z-
dc.date.available2008-06-12T06:31:12Z-
dc.date.issued2000en_HK
dc.identifier.citationProtein Science, 2000, v. 9 n. 4, p. 671-682en_HK
dc.identifier.issn0961-8368en_HK
dc.identifier.urihttp://hdl.handle.net/10722/48976-
dc.description.abstractThe backbone dynamics of the four-helical bundle cytokine leukemia inhibitory factor (LIF) have been investigated using 15N NMR relaxation and amide proton exchange measurements on a murine-human chimera, MH35-LIF. For rapid backbone motions (on a time scale of 10 ps to 100 ns), as probed by 15N relaxation measurements, the dynamics parameters were calculated using the model-free formalism incorporating the model selection approach. The principal components of the inertia tensor of MH35-LIF, as calculated from its NMR structure, were 1:0.98:0.38. The global rotational motion of the molecule was, therefore, assumed to be axially symmetric in the analysis of its relaxation data. This yielded a diffusion anisotropy D(parallel)/D(perpendicular) of 1.31 and an effective correlation time (4D(perpendicular) + 2D(parallel))(-1) of 8.9 ns. The average values of the order parameters (S2) for the four helices, the long interhelical loops, and the N-terminus were 0.91, 0.84, and 0.65, respectively, indicating that LIF is fairly rigid in solution, except at the N-terminus. The S2 values for the long interhelical loops of MH35-LIF were higher than those of their counterparts in short-chain members of the four-helical bundle cytokine family. Residues involved in LIF receptor binding showed no consistent pattern of backbone mobilities, with S2 values ranging from 0.71 to 0.95, but residues contributing to receptor binding site III had relatively lower S2 values, implying higher amplitude motions than for the backbone of sites I and II. In the relatively slow motion regime, backbone amide exchange measurements showed that a number of amides from the helical bundle exchanged extremely slowly, persisting for several months in 2H2O at 37 degrees C. Evidence for local unfolding was considered, and correlations among various structure-related parameters and the backbone amide exchange rates were examined. Both sets of data concur in showing that LIF is one of the most rigid four-helical bundle cytokines.en_HK
dc.format.extent388 bytes-
dc.format.mimetypetext/html-
dc.languageengen_HK
dc.publisherCold Spring Harbor Laboratory Press, Publications Department. The Journal's web site is located at http://www.proteinscience.org/en_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectAmide exchangeen_HK
dc.subjectCytokineen_HK
dc.subjectLeukemia inhibitory factoren_HK
dc.subject15N relaxationen_HK
dc.subjectNMRen_HK
dc.titleBackbone dynamics measurements on leukemia inhibitory factor, a rigid four-helical bundle cytokineen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0961-8368&volume=9&issue=4&spage=671&epage=682&date=2000&atitle=Backbone+dynamics+measurements+on+leukemia+inhibitory+factor,+a+rigid+four-helical+bundle+cytokineen_HK
dc.identifier.emailSmith, DK: dsmith@hkucc.hku.hken_HK
dc.description.naturepublished_or_final_versionen_HK
dc.identifier.pmid10794409-
dc.identifier.pmcidPMC2144613en_HK
dc.identifier.scopuseid_2-s2.0-0034087684-
dc.identifier.hkuros51696-
dc.identifier.isiWOS:000086505200005-

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