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Article: Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase

TitleStructural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase
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. 40, p. 27637-27645 How to Cite?
AbstractCyclic ADP-ribose (cADPR) is a universal calcium messenger molecule that regulatesmanyphysiological processes.Theproduction and degradation of cADPR are catalyzed by a family of related enzymes, including the ADP-ribosyl cyclase from Aplysia california (ADPRAC) and CD38 from human. Although ADPRC and CD38 share a common evolutionary ancestor, their enzymatic functions toward NAD and cADPR homeostasis have evolved divergently. Thus, ADPRC can only generate cADPR from NAD (cyclase), whereas CD38, in contrast, has multiple activities, i.e. in cADPR production and degradation, as well as NAD hydrolysis (NADase). In this study, we determined a number of ADPRC and CD38structures bound with various nucleotides. From these complexes, we elucidated the structural features required for the cyclization (cyclase) reaction of ADPRC and the NADase reaction of CD38. Using the structural approach in combination with site-directed mutagenesis, we identified Phe-174 in ADPRC as a critical residue in directing the folding of the substrate during the cyclization reaction. Thus, a point mutation ofPhe-174to glycinecanturn ADPRC from a cyclase toward an NADase. The equivalent residue in CD38, Thr-221, is shown to disfavor the cyclizing folding of the substrate, resulting in NADase being the dominant activity. The comprehensive structural comparison of CD38 and APDRC presented in this study thus provides insights into the structural determinants for the functional evolution from a cyclase to a hydrolase. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/123989
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthGM061568
National Science Foundation of China/Research Grant Council of Hong Kong (NSFC/RGC) Joint Research Scheme
Wellcome Trust084068
Dreyfus Foundation New Faculty Award
Funding Information:

This work was supported, in whole or in part, by National Institutes of Health Grant GM061568 (to H. C. L. and Q. H.). This work was also supported by Hong Kong General Research Fund grants from the National Science Foundation of China/Research Grant Council of Hong Kong (NSFC/RGC) Joint Research Scheme (to Q. H. and H. C. L.), Project Grant 084068 from the Wellcome Trust (to B. V. L. P.), and the Dreyfus Foundation New Faculty Award (to H. L.).

References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Qen_HK
dc.contributor.authorGraeff, Ren_HK
dc.contributor.authorKriksunov, IAen_HK
dc.contributor.authorJiang, Hen_HK
dc.contributor.authorZhang, Ben_HK
dc.contributor.authorOppenheimer, Nen_HK
dc.contributor.authorLin, Hen_HK
dc.contributor.authorPotter, BVLen_HK
dc.contributor.authorLee, HCen_HK
dc.contributor.authorHao, Qen_HK
dc.date.accessioned2010-10-15T08:04:42Z-
dc.date.available2010-10-15T08:04:42Z-
dc.date.issued2009en_HK
dc.identifier.citationJournal Of Biological Chemistry, 2009, v. 284 n. 40, p. 27637-27645en_HK
dc.identifier.issn0021-9258en_HK
dc.identifier.urihttp://hdl.handle.net/10722/123989-
dc.description.abstractCyclic ADP-ribose (cADPR) is a universal calcium messenger molecule that regulatesmanyphysiological processes.Theproduction and degradation of cADPR are catalyzed by a family of related enzymes, including the ADP-ribosyl cyclase from Aplysia california (ADPRAC) and CD38 from human. Although ADPRC and CD38 share a common evolutionary ancestor, their enzymatic functions toward NAD and cADPR homeostasis have evolved divergently. Thus, ADPRC can only generate cADPR from NAD (cyclase), whereas CD38, in contrast, has multiple activities, i.e. in cADPR production and degradation, as well as NAD hydrolysis (NADase). In this study, we determined a number of ADPRC and CD38structures bound with various nucleotides. From these complexes, we elucidated the structural features required for the cyclization (cyclase) reaction of ADPRC and the NADase reaction of CD38. Using the structural approach in combination with site-directed mutagenesis, we identified Phe-174 in ADPRC as a critical residue in directing the folding of the substrate during the cyclization reaction. Thus, a point mutation ofPhe-174to glycinecanturn ADPRC from a cyclase toward an NADase. The equivalent residue in CD38, Thr-221, is shown to disfavor the cyclizing folding of the substrate, resulting in NADase being the dominant activity. The comprehensive structural comparison of CD38 and APDRC presented in this study thus provides insights into the structural determinants for the functional evolution from a cyclase to a hydrolase. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.en_HK
dc.languageeng-
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.subject.meshADP-ribosyl Cyclase - chemistry - genetics - metabolism-
dc.subject.meshEvolution, Molecular-
dc.subject.meshInosine Nucleotides - metabolism-
dc.subject.meshNAD - metabolism-
dc.subject.meshProtein Conformation-
dc.titleStructural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolaseen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0021-9258&volume=284&issue=40&spage=27637&epage=27645&date=2009&atitle=Structural+basis+for+enzymatic+evolution+from+a+dedicated+ADP-ribosyl+cyclase+to+a+multifunctional+NAD+hydrolase-
dc.identifier.emailGraeff, R: graeffr@hku.hken_HK
dc.identifier.emailLee, HC: leehc@hku.hken_HK
dc.identifier.emailHao, Q: qhao@hku.hken_HK
dc.identifier.authorityGraeff, R=rp01464en_HK
dc.identifier.authorityLee, HC=rp00545en_HK
dc.identifier.authorityHao, Q=rp01332en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1074/jbc.M109.031005en_HK
dc.identifier.pmid19640846-
dc.identifier.pmcidPMC2785692-
dc.identifier.scopuseid_2-s2.0-70350437285en_HK
dc.identifier.hkuros167634-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-70350437285&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume284en_HK
dc.identifier.issue40en_HK
dc.identifier.spage27637en_HK
dc.identifier.epage27645en_HK
dc.identifier.eissn1083-351X-
dc.identifier.isiWOS:000270232300065-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLiu, Q=35215401600en_HK
dc.identifier.scopusauthoridGraeff, R=7003614053en_HK
dc.identifier.scopusauthoridKriksunov, IA=6507909504en_HK
dc.identifier.scopusauthoridJiang, H=27171339900en_HK
dc.identifier.scopusauthoridZhang, B=8216128800en_HK
dc.identifier.scopusauthoridOppenheimer, N=7004639543en_HK
dc.identifier.scopusauthoridLin, H=8686527600en_HK
dc.identifier.scopusauthoridPotter, BVL=16073310200en_HK
dc.identifier.scopusauthoridLee, HC=26642959100en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK

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