| Structural highlights
8pms is a 4 chain structure with sequence from Aspergillus fumigatus Af293. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.4Å |
| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
NADA_ASPFU Conidial surface nicotinamide adenine dinucleotide glycohydrolase that cleave NAD(+) and NADP(+) but not their reduced counterparts, NADH and NADPH (PubMed:33712585). Lacks both ADP-ribosyl cyclase and base exchange activity and does not mediate synthesis of calcium messengers cADPR or NAADP (PubMed:33712585). Plays a role in pathogenicity by depleting the host's NAD(+) pool (PubMed:33712585).[1]
Publication Abstract from PubMed
Nicotinamide adenine dinucleotide (NAD) is an essential molecule in all kingdoms of life, mediating energy metabolism and cellular signaling. Recently, a new class of highly active fungal surface NADases was discovered. The enzyme from the opportunistic human pathogen Aspergillus fumigatus was thoroughly characterized. It harbors a catalytic domain that resembles that of the tuberculosis necrotizing toxin from Mycobacterium tuberculosis, which efficiently cleaves NAD(+) to nicotinamide and ADP-ribose, thereby depleting the dinucleotide pool. Of note, the A. fumigatus NADase has an additional Ca(2+)-binding motif at the C-terminus of the protein. Despite the presence of NADases in several fungal divisions, the Ca(2+)-binding motif is uniquely found in the Eurotiales order, which contains species that have immense health and economic impacts on humans. To identify the potential roles of the metal ion-binding site in catalysis or protein stability, we generated and characterized A. fumigatus NADase variants lacking the ability to bind calcium. X-ray crystallographic analyses revealed that the mutation causes a drastic and dynamic structural rearrangement of the homodimer, resulting in decreased thermal stability. Even though the calcium-binding site is at a long distance from the catalytic center, the structural reorganization upon the loss of calcium binding allosterically alters the active site, thereby negatively affecting NAD-glycohydrolase activity. Together, these findings reveal that this unique calcium-binding site affects the protein fold, stabilizing the dimeric structure, but also mediates long-range effects resulting in an increased catalytic rate.
Novel Calcium-Binding Motif Stabilizes and Increases the Activity of Aspergillus fumigatus Ecto-NADase.,Ferrario E, Kallio JP, Stromland O, Ziegler M Biochemistry. 2023 Nov 21;62(22):3293-3302. doi: 10.1021/acs.biochem.3c00360. , Epub 2023 Nov 7. PMID:37934975[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Stromland O, Kallio JP, Pschibul A, Skoge RH, Harethardottir HM, Sverkeli LJ, Heinekamp T, Kniemeyer O, Migaud M, Makarov MV, Gossmann TI, Brakhage AA, Ziegler M. Discovery of fungal surface NADases predominantly present in pathogenic species. Nat Commun. 2021 Mar 12;12(1):1631. doi: 10.1038/s41467-021-21307-z. PMID:33712585 doi:http://dx.doi.org/10.1038/s41467-021-21307-z
- ↑ Ferrario E, Kallio JP, Strømland Ø, Ziegler M. Novel Calcium-Binding Motif Stabilizes and Increases the Activity of Aspergillus fumigatus Ecto-NADase. Biochemistry. 2023 Nov 7. PMID:37934975 doi:10.1021/acs.biochem.3c00360
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