Abstract
Cyclic ADP-ribose (cADPR) mobilizes intracellular Ca2+ stores and activates Ca2+ influx to regulate a wide range of physiological processes. It is one of the products produced from the catalysis of NAD+ by the multifunctional CD38/ADP-ribosyl cyclase superfamily. After elimination of the nicotinamide ring by the enzyme, the reaction intermediate of NAD+ can either be hydrolyzed to form linear ADPR or cyclized to form cADPR. We have previously shown that human CD38 exhibits a higher preference towards the hydrolysis of NAD+ to form linear ADPR while Aplysia ADP-ribosyl cyclase prefers cyclizing NAD+ to form cADPR. In this study, we characterized the enzymatic properties of porcine CD38 and revealed that it has a prominent secondary NAD+ cyclase activity producing cADPR. We also determined the X-ray crystallographic structures of porcine CD38 and were able to observe conformational flexibility at the base of the active site of the enzyme which allow the NAD+ reaction intermediate to adopt conformations resulting in both hydrolysis and cyclization forming linear ADPR and cADPR respectively.
Original language | English (US) |
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Pages (from-to) | 650-661 |
Number of pages | 12 |
Journal | Protein Science |
Volume | 25 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2016 |
Bibliographical note
Publisher Copyright:© 2015 The Protein Society.
Keywords
- CD38
- NAD cyclization
- X-ray crystallography
- cyclic ADP-ribose
- secondary enzyme activity