8R17

Crystal structure of Neurospora crassa NADase with modified C-terminus

8R17 の概要

• エントリーDOI: 10.2210/pdb8r17/pdb
• 分子名称: Conidial surface nicotinamide adenine dinucleotide glycohydrolase,Conidial surface nicotinamide adenine dinucleotide glycohydrolase nadA, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: nadase, nad hydrolase, homodimer, glycoprotein, extracellular, tnt domain, hydrolase
• 由来する生物種: Neurospora crassa; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29234.33

構造登録者

Kallio, J.P.,Ferrario, E.,Ziegler, M. (登録日: 2023-11-01, 公開日: 2024-07-03, 最終更新日: 2024-11-13)

主引用文献

Ferrario, E.,Kallio, J.P.,Emdadi, M.,Stromland, O.,Rack, J.G.M.,Ziegler, M.
Evolution of fungal tuberculosis necrotizing toxin (TNT) domain-containing enzymes reveals divergent adaptations to enhance NAD cleavage.
Protein Sci., 33:e5071-e5071, 2024

PubMed Abstract: Tuberculosis 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 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.

PubMed: 38895984
DOI: 10.1002/pro.5071

実験手法

X-RAY DIFFRACTION (2.3 Å)