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| | {{STRUCTURE_2hct| PDB=2hct | SCENE= }} | | {{STRUCTURE_2hct| PDB=2hct | SCENE= }} |
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| - | '''Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine NAAPD synthesis and hydrolysis activities'''
| + | ===Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine NAAPD synthesis and hydrolysis activities=== |
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| - | ==Overview==
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| - | Nicotinic acid adenine dinucleotide phosphate (NAADP) is a novel metabolite of NADP that has now been established as a Ca(2+) messenger in many cellular systems. Its synthesis is catalyzed by multifunctional enzymes, CD38 and ADP-ribosyl cyclase (cyclase). The degradation pathway for NAADP is unknown and no enzyme that can specifically hydrolyze it has yet been identified. Here we show that CD38 can, in fact, hydrolyze NAADP to ADP-ribose 2'-phosphate. This activity was low at neutrality but greatly increased at acidic pH. This novel pH dependence suggests that the hydrolysis is determined by acidic residues at the active site. X-ray crystallography of the complex of CD38 with one of its substrates, NMN, showed that the nicotinamide moiety was in close contact with Glu(146) at 3.27 A and Asp(155) at 2.52 A. Changing Glu(146) to uncharged Gly and Ala, and Asp(155) to Gln and Asn, by site-directed mutagenesis indeed eliminated the strong pH dependence. Changing Asp(155) to Glu, in contrast, preserved the dependence. The specificity of the two acidic residues was further demonstrated by changing the adjacent Asp(147) to Val, which had minimal effect on the pH dependence. Crystallography confirmed that Asp(147) was situated and directed away from the bound substrate. Synthesis of NAADP catalyzed by CD38 is known to have strong preference for acidic pH, suggesting that Glu(146) and Asp(155) are also critical determinants. This was shown to be case by mutagensis. Likewise, using similar approaches, Glu(98) of the cyclase, which is equivalent to Glu(146) in CD38, was found to be responsible for controlling the pH dependence of NAADP synthesis by the cyclase. Based on these findings, a catalytic model is proposed.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_16861223}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 16861223 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_16861223}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Alpha bundle]] | | [[Category: Alpha bundle]] |
| | [[Category: Beta sheet]] | | [[Category: Beta sheet]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 06:07:55 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 03:12:27 2008'' |
Revision as of 00:12, 28 July 2008
Template:STRUCTURE 2hct
Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine NAAPD synthesis and hydrolysis activities
Template:ABSTRACT PUBMED 16861223
About this Structure
2HCT is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Acidic residues at the active sites of CD38 and ADP-ribosyl cyclase determine nicotinic acid adenine dinucleotide phosphate (NAADP) synthesis and hydrolysis activities., Graeff R, Liu Q, Kriksunov IA, Hao Q, Lee HC, J Biol Chem. 2006 Sep 29;281(39):28951-7. Epub 2006 Jul 21. PMID:16861223
Page seeded by OCA on Mon Jul 28 03:12:27 2008
