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Article: The membrane-bound enzyme CD38 exists in two opposing orientations

TitleThe membrane-bound enzyme CD38 exists in two opposing orientations
Authors
Issue Date2012
PublisherAmerican Association for the Advancement of Science.
Citation
Sci Signal., 2012, v. 5 n. 241, p. ra67 How to Cite?
AbstractThe transmembrane enzyme CD38, a multifunctional protein ubiquitously present in cells, is the main enzyme that synthesizes and hydrolyzes cyclic adenosine 5'-diphosphate-ribose (cADPR), an intracellular Ca(2+)-mobilizing messenger. CD38 is thought to be a type II transmembrane protein with its carboxyl-terminal catalytic domain located on the outside of the cell; thus, the mechanism by which CD38 metabolizes intracellular cADPR has been controversial. We developed specific antibodies against the amino-terminal segment of CD38 and showed that two opposing orientations of CD38, type II and type III (which has its catalytic domain inside the cell), were both present on the surface of HL-60 cells during retinoic acid-induced differentiation. When activated by interferon-gamma, human primary monocytes and the monocytic U937 cell line exhibited a similar co-distribution pattern. Site-directed mutagenesis experiments showed that the membrane orientation of CD38 could be converted from a mixture of type II and type III orientations to all type III by mutating the cationic amino acid residues in the amino-terminal segment of CD38. Expression of type III CD38 construct in transfected cells led to increased intracellular concentrations of cADPR, indicating the importance of the type III orientation of CD38 to its Ca(2+) signaling function. The identification of these two forms of CD38 suggests that flipping the catalytic domain from the outside to the inside of the cell may be a mechanism regulating its signaling activity.
Persistent Identifierhttp://hdl.handle.net/10722/189348
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhao, Yen_US
dc.contributor.authorLam, MCen_US
dc.contributor.authorLee, HCen_US
dc.date.accessioned2013-09-17T14:36:44Z-
dc.date.available2013-09-17T14:36:44Z-
dc.date.issued2012en_US
dc.identifier.citationSci Signal., 2012, v. 5 n. 241, p. ra67en_US
dc.identifier.urihttp://hdl.handle.net/10722/189348-
dc.description.abstractThe transmembrane enzyme CD38, a multifunctional protein ubiquitously present in cells, is the main enzyme that synthesizes and hydrolyzes cyclic adenosine 5'-diphosphate-ribose (cADPR), an intracellular Ca(2+)-mobilizing messenger. CD38 is thought to be a type II transmembrane protein with its carboxyl-terminal catalytic domain located on the outside of the cell; thus, the mechanism by which CD38 metabolizes intracellular cADPR has been controversial. We developed specific antibodies against the amino-terminal segment of CD38 and showed that two opposing orientations of CD38, type II and type III (which has its catalytic domain inside the cell), were both present on the surface of HL-60 cells during retinoic acid-induced differentiation. When activated by interferon-gamma, human primary monocytes and the monocytic U937 cell line exhibited a similar co-distribution pattern. Site-directed mutagenesis experiments showed that the membrane orientation of CD38 could be converted from a mixture of type II and type III orientations to all type III by mutating the cationic amino acid residues in the amino-terminal segment of CD38. Expression of type III CD38 construct in transfected cells led to increased intracellular concentrations of cADPR, indicating the importance of the type III orientation of CD38 to its Ca(2+) signaling function. The identification of these two forms of CD38 suggests that flipping the catalytic domain from the outside to the inside of the cell may be a mechanism regulating its signaling activity.en_US
dc.languageengen_US
dc.publisherAmerican Association for the Advancement of Science.en_US
dc.relation.ispartofSci Signal.en_US
dc.rightsSci Signal.. Copyright © American Association for the Advancement of Science.en_US
dc.subject.meshAntigens, CD38 - genetics - metabolismen_US
dc.subject.meshCalcium - metabolismen_US
dc.subject.meshCalcium Signaling - drug effects - physiologyen_US
dc.subject.meshCyclic ADP-Ribose - metabolismen_US
dc.subject.meshMembrane Glycoproteins - genetics - metabolismen_US
dc.titleThe membrane-bound enzyme CD38 exists in two opposing orientationsen_US
dc.typeArticleen_US
dc.identifier.emailZhao, Y: yongjuan@hkucc.hku.hken_US
dc.identifier.emailLam, MC: lammo@hkucc.hku.hken_US
dc.identifier.emailLee, HC: leehc@hku.hken_US
dc.identifier.authorityLee, HC=rp00545en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1126/scisignal.2002700en_US
dc.identifier.pmid22969159en_US
dc.identifier.hkuros222838en_US
dc.identifier.hkuros202950-
dc.identifier.volume5en_US
dc.identifier.issue241en_US
dc.identifier.spagera67en_US
dc.identifier.epagera67en_US
dc.identifier.isiWOS:000308801500003-
dc.publisher.placeWashington DCen_US

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