8r17
Crystal structure of Neurospora crassa NADase with modified C-terminus
Structural highlights
FunctionNADA_NEUCR Conidial surface nicotinamide adenine dinucleotide glycohydrolase that cleave NAD(+) and NADP(+) but not their reduced counterparts, NADH and NADPH (PubMed:33712585, PubMed:6260480). Lacks both ADP-ribosyl cyclase and base exchange activity and does not mediate synthesis of calcium messengers cADPR or NAADP (PubMed:33712585). Its function is correlated with aerial hyphae formation and conidiogenesis, but its physiological role is still obscure (PubMed:131723, PubMed:165174). Is able to ADP-ribosylate itself for self-inactivation (PubMed:9787786).[1] [2] [3] [4] [5] 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).[6] Publication Abstract from PubMedTuberculosis necrotizing toxin (TNT) is a protein domain discovered on the outer membrane of Mycobacterium tuberculosis (Mtb), and the fungal pathogen Aspergillus fumigatus. TNT domains have pure NAD(P) hydrolytic activity, setting them apart from other NAD-cleaving domains such as ADP-ribosyl cyclase and Toll/interleukin-1 receptor homology (TIR) domains which form a wider set of products. Importantly, the Mtb TNT domain has been shown to be involved in immune evasion via depletion of the intracellular NAD pool of macrophages. Therefore, an intriguing hypothesis is that TNT domains act as "NAD killers" in host cells facilitating pathogenesis. Here, we explore the phylogenetic distribution of TNT domains and detect their presence solely in bacteria and fungi. Within fungi, we discerned six TNT clades. In addition, X-ray crystallography and AlphaFold2 modeling unveiled clade-specific strategies to promote homodimer stabilization of the fungal enzymes, namely, Ca(2+) binding, disulfide bonds, or hydrogen bonds. We show that dimer stabilization is a requirement for NADase activity and that the group-specific strategies affect the active site conformation, thereby modulating enzyme activity. Together, these findings reveal the evolutionary lineage of fungal TNT enzymes, corroborating the hypothesis of them being pure extracellular NAD (eNAD) cleavers, with possible involvement in microbial warfare and host immune evasion. Evolution of fungal tuberculosis necrotizing toxin (TNT) domain-containing enzymes reveals divergent adaptations to enhance NAD cleavage.,Ferrario E, Kallio JP, Emdadi M, Stromland O, Rack JGM, Ziegler M Protein Sci. 2024 Jul;33(7):e5071. doi: 10.1002/pro.5071. PMID:38895984[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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