File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: A highly conserved motif within the NH2-terminal coiled-coil domain of angiopoietin-like protein 4 confers its inhibitory effects on lipoprotein lipase by disrupting the enzyme dimerization

TitleA highly conserved motif within the NH2-terminal coiled-coil domain of angiopoietin-like protein 4 confers its inhibitory effects on lipoprotein lipase by disrupting the enzyme dimerization
Authors
Issue Date2009
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 2009, v. 284 n. 18, p. 11942-11952 How to Cite?
AbstractLipoprotein lipase (LPL) is a principal enzyme responsible for the clearance of chylomicrons and very low density lipoproteins from the bloodstream. Two members of the Angptl (angiopoietin-like protein) family, namely Angptl3 and Angptl4, have been shown to inhibit LPL activity in vitro and in vivo. Here, we further investigated the structural basis underlying the LPL inhibition by Angptl3 and Angptl4. By multiple sequence alignment analysis, we have identified a highly conserved 12-amino acid consensus motif that is present within the coiled-coil domain (CCD) of both Angptl3 and Angptl4, but not other members of the Angptl family. Substitution of the three polar amino acid residues (His46, Gln50, and Gln53) within this motif with alanine abolishes the inhibitory effect of Angptl4 on LPL in vitro and also abrogates the ability of Angptl4 to elevate plasma triglyceride levels in mice. The CCD of Angptl4 interacts with LPL and converts the catalytically active dimers of LPL to its inactive monomers, whereas the mutant protein with the three polar amino acids being replaced by alanine loses such a property. Furthermore, a synthetic peptide consisting of the 12-amino acid consensus motif is sufficient to inhibit LPL activity, although the potency is much lower than the recombinant CCD of Angptl4. In summary, our data suggest that the 12-amino acid consensus motif within the CCD of Angptl4, especially the three polar residues within this motif, is responsible for its interaction with and inhibition of LPL by blocking the enzyme dimerization. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/163249
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYau, MHen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorZhang, Jen_HK
dc.contributor.authorWu, Den_HK
dc.contributor.authorXu, Aen_HK
dc.date.accessioned2012-09-05T05:29:08Z-
dc.date.available2012-09-05T05:29:08Z-
dc.date.issued2009en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2009, v. 284 n. 18, p. 11942-11952en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/163249-
dc.description.abstractLipoprotein lipase (LPL) is a principal enzyme responsible for the clearance of chylomicrons and very low density lipoproteins from the bloodstream. Two members of the Angptl (angiopoietin-like protein) family, namely Angptl3 and Angptl4, have been shown to inhibit LPL activity in vitro and in vivo. Here, we further investigated the structural basis underlying the LPL inhibition by Angptl3 and Angptl4. By multiple sequence alignment analysis, we have identified a highly conserved 12-amino acid consensus motif that is present within the coiled-coil domain (CCD) of both Angptl3 and Angptl4, but not other members of the Angptl family. Substitution of the three polar amino acid residues (His46, Gln50, and Gln53) within this motif with alanine abolishes the inhibitory effect of Angptl4 on LPL in vitro and also abrogates the ability of Angptl4 to elevate plasma triglyceride levels in mice. The CCD of Angptl4 interacts with LPL and converts the catalytically active dimers of LPL to its inactive monomers, whereas the mutant protein with the three polar amino acids being replaced by alanine loses such a property. Furthermore, a synthetic peptide consisting of the 12-amino acid consensus motif is sufficient to inhibit LPL activity, although the potency is much lower than the recombinant CCD of Angptl4. In summary, our data suggest that the 12-amino acid consensus motif within the CCD of Angptl4, especially the three polar residues within this motif, is responsible for its interaction with and inhibition of LPL by blocking the enzyme dimerization. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.en_HK
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_HK
dc.relation.ispartofJournal of Biological Chemistryen_HK
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.-
dc.subject.mesh3T3-L1 Cellsen_US
dc.subject.meshAmino Acid Motifs - Physiologyen_US
dc.subject.meshAmino Acid Substitutionen_US
dc.subject.meshAngiopoietins - Genetics - Metabolismen_US
dc.subject.meshAnimalsen_US
dc.subject.meshDimerizationen_US
dc.subject.meshEnzyme Inhibitors - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshLipoprotein Lipase - Antagonists & Inhibitors - Genetics - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMutationen_US
dc.subject.meshPeptide Mapping - Methodsen_US
dc.subject.meshProtein Structure, Tertiary - Physiologyen_US
dc.subject.meshSequence Alignment - Methodsen_US
dc.titleA highly conserved motif within the NH2-terminal coiled-coil domain of angiopoietin-like protein 4 confers its inhibitory effects on lipoprotein lipase by disrupting the enzyme dimerizationen_HK
dc.typeArticleen_HK
dc.identifier.emailWang, Y: yuwanghk@hku.hken_HK
dc.identifier.emailLam, KSL: ksllam@hku.hken_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.identifier.authorityLam, KSL=rp00343en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.M809802200en_HK
dc.identifier.pmid19246456en_HK
dc.identifier.scopuseid_2-s2.0-66449084528en_HK
dc.identifier.hkuros155395-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66449084528&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume284en_HK
dc.identifier.issue18en_HK
dc.identifier.spage11942en_HK
dc.identifier.epage11952en_HK
dc.identifier.isiWOS:000265494600026-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYau, MH=9233223900en_HK
dc.identifier.scopusauthoridWang, Y=34973733700en_HK
dc.identifier.scopusauthoridLam, KSL=8082870600en_HK
dc.identifier.scopusauthoridZhang, J=35504391800en_HK
dc.identifier.scopusauthoridWu, D=7404297751en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats