| Structural highlights
Function
ABTIR_ACIB9 NAD(+) hydrolase (NADase) that catalyzes cleavage of NAD(+) into ADP-D-ribose (ADPR) and nicotinamide (PubMed:29395922). In addition to ADPR, also generates a cyclization variant of cyclic ADPR (cADPR), termed 2'cADPR (v-cADPR) (PubMed:29395922, PubMed:36048923). Cleaves NADP(+), but does not cyclize the product (PubMed:36048923).[1] [2]
Publication Abstract from PubMed
Toll-like and Interleukin-1/18 receptor resistance (TIR) domain-containing proteins function as important signaling and immune regulatory molecules. TIR domain-containing proteins identified in eukaryotic and prokaryotic species also exhibit NAD+ hydrolase activity in select bacteria, plants, and mammalian cells. We report the crystal structure of the Acinetobacter baumannii TIR domain protein (AbTir-TIR) with confirmed NAD(+) hydrolysis and map the conformational effects of its interaction with NAD(+) using hydrogen-deuterium exchange-mass spectrometry (HDX-MS). NAD(+) results in mild decreases in deuterium uptake at the dimeric interface. In addition, AbTir-TIR exhibits EX1 kinetics indicative of large cooperative conformational changes which are slowed down upon substrate binding. Additionally, we have developed label-free imaging using the minimally invasive spectroscopic method 2p-FLIM which shows differences in bacteria expressing native and mutant NAD+ hydrolase-inactivated AbTir-TIR(E208A) protein. Our observations are consistent with substrate-induced conformational changes reported in other TIR model systems with NAD+ hydrolase activity. These studies provide further insight into bacterial TIR protein mechanisms and their varying roles in biology.
The structure of NAD(+) consuming protein Acinetobacter baumannii TIR domain shows unique kinetics and conformations.,Klontz E, Obi JO, Wang Y, Glendening G, Carr J, Tsibouris C, Buddula S, Nallar S, Soares AS, Beckett D, Redzic JS, Eisenmesser E, Palm C, Schmidt K, Scudder AH, Obiorah T, Essuman K, Milbrandt J, Diantonio A, Ray K, Snyder MLD, Deredge D, Snyder GA J Biol Chem. 2023 Sep 25:105290. doi: 10.1016/j.jbc.2023.105290. PMID:37758001[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Essuman K, Summers DW, Sasaki Y, Mao X, Yim AKY, DiAntonio A, Milbrandt J. TIR Domain Proteins Are an Ancient Family of NAD(+)-Consuming Enzymes. Curr Biol. 2018 Feb 5;28(3):421-430.e4. doi: 10.1016/j.cub.2017.12.024. Epub 2018 , Jan 25. PMID:29395922 doi:http://dx.doi.org/10.1016/j.cub.2017.12.024
- ↑ Manik MK, Shi Y, Li S, Zaydman MA, Damaraju N, Eastman S, Smith TG, Gu W, Masic V, Mosaiab T, Weagley JS, Hancock SJ, Vasquez E, Hartley-Tassell L, Kargios N, Maruta N, Lim BYJ, Burdett H, Landsberg MJ, Schembri MA, Prokes I, Song L, Grant M, DiAntonio A, Nanson JD, Guo M, Milbrandt J, Ve T, Kobe B. Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling. Science. 2022 Sep 30;377(6614):eadc8969. PMID:36048923 doi:10.1126/science.adc8969
- ↑ Klontz E, Obi JO, Wang Y, Glendening G, Carr J, Tsibouris C, Buddula S, Nallar S, Soares AS, Beckett D, Redzic JS, Eisenmesser E, Palm C, Schmidt K, Scudder AH, Obiorah T, Essuman K, Milbrandt J, Diantonio A, Ray K, Snyder MLD, Deredge D, Snyder GA. The structure of NAD(+) consuming protein Acinetobacter baumannii TIR domain shows unique kinetics and conformations. J Biol Chem. 2023 Sep 25:105290. PMID:37758001 doi:10.1016/j.jbc.2023.105290
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