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Article: Conformational closure of the catalytic site of human CD38 induced by calcium

TitleConformational closure of the catalytic site of human CD38 induced by calcium
Authors
Issue Date2008
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2008, v. 47 n. 52, p. 13966-13973 How to Cite?
AbstractFirst identified on the surface of lymphoids as a type II transmembrane protein, CD38 has now been established to have dual functions not only as a receptor but also as a multifunctional enzyme, catalyzing the synthesis of and hydrolysis of a general calcium messenger molecule, cyclic ADP-ribose (cADPR). The receptorial functions of CD38 include the induction of cell adhesion, differentiation, apoptosis, and cytokine production upon antibody ligation. Here we determined the crystal structure of calcium-loaded human CD38 at 1.45 Å resolution which reveals that CD38 undergoes dramatic structural changes to an inhibited conformation in the presence of calcium. The structural changes are highly localized and occur in only two regions. The first region is part of the active site and consists of residues 121-141. In the presence of calcium, W125 moves 5 Å into the active site and forms hydrophobic interactions with W189. The movement closes the active site pocket and reduces entry of substrates, resulting in inhibition of the enzymatic activity. The structural role of calcium in inducing these conformational changes is readily visualized in the crystal structure. The other region that undergoes calcium-induced changes is at the receptor region, where a highly ordered helix is unraveled to a random coil. The results suggest a novel conformational coupling mechanism, whereby protein interaction targeted at the receptor region can effectively regulate the enzymatic activity of CD38. © 2008 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/59673
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
Funding AgencyGrant Number
NIHRR01646
GM061568
RGCHKU-769107M
Funding Information:

This work was supported by grants from the NIH to MacCHESS (RR01646) and H.C.L./Q.H. (GM061568) and by RGC Grant HKU-769107M.

References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Qen_HK
dc.contributor.authorGraeff, Ren_HK
dc.contributor.authorKriksunov, IAen_HK
dc.contributor.authorLam, CMCen_HK
dc.contributor.authorLee, HCen_HK
dc.contributor.authorHao, Qen_HK
dc.date.accessioned2010-05-31T03:54:59Z-
dc.date.available2010-05-31T03:54:59Z-
dc.date.issued2008en_HK
dc.identifier.citationBiochemistry, 2008, v. 47 n. 52, p. 13966-13973en_HK
dc.identifier.issn0006-2960en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59673-
dc.description.abstractFirst identified on the surface of lymphoids as a type II transmembrane protein, CD38 has now been established to have dual functions not only as a receptor but also as a multifunctional enzyme, catalyzing the synthesis of and hydrolysis of a general calcium messenger molecule, cyclic ADP-ribose (cADPR). The receptorial functions of CD38 include the induction of cell adhesion, differentiation, apoptosis, and cytokine production upon antibody ligation. Here we determined the crystal structure of calcium-loaded human CD38 at 1.45 Å resolution which reveals that CD38 undergoes dramatic structural changes to an inhibited conformation in the presence of calcium. The structural changes are highly localized and occur in only two regions. The first region is part of the active site and consists of residues 121-141. In the presence of calcium, W125 moves 5 Å into the active site and forms hydrophobic interactions with W189. The movement closes the active site pocket and reduces entry of substrates, resulting in inhibition of the enzymatic activity. The structural role of calcium in inducing these conformational changes is readily visualized in the crystal structure. The other region that undergoes calcium-induced changes is at the receptor region, where a highly ordered helix is unraveled to a random coil. The results suggest a novel conformational coupling mechanism, whereby protein interaction targeted at the receptor region can effectively regulate the enzymatic activity of CD38. © 2008 American Chemical Society.en_HK
dc.languageengen_HK
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_HK
dc.relation.ispartofBiochemistryen_HK
dc.titleConformational closure of the catalytic site of human CD38 induced by calciumen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-2960&volume=47&spage=13966&epage=13973&date=2008&atitle=Conformational+closure+of+the+catalytic+site+of+human+CD38+induced+by+calcium.en_HK
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_subscribed_fulltexten_US
dc.identifier.doi10.1021/bi801642qen_HK
dc.identifier.pmid19117080-
dc.identifier.scopuseid_2-s2.0-58849105013en_HK
dc.identifier.hkuros154346en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-58849105013&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume47en_HK
dc.identifier.issue52en_HK
dc.identifier.spage13966en_HK
dc.identifier.epage13973en_HK
dc.identifier.isiWOS:000262032600024-
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.scopusauthoridLam, CMC=26026006700en_HK
dc.identifier.scopusauthoridLee, HC=26642959100en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK

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