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TitleDissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 6218, Year 2024
Publish dateJul 23, 2024
AuthorsSanghyeon Choi / Youngjin Lee / Shinhye Park / Song Yee Jang / Jongbin Park / Do Won Oh / Su-Man Kim / Tae-Hwan Kim / Ga Seul Lee / Changyi Cho / Byoung Sik Kim / Donghan Lee / Eun-Hee Kim / Hae-Kap Cheong / Jeong Hee Moon / Ji-Joon Song / Jungwon Hwang / Myung Hee Kim /
PubMed AbstractMultiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly ...Multiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly opportunistic pathogen that causes primary septicemia, the precursor of sepsis, is a major driver of infection; however, the molecular mechanism via which the toxin contributes to septicemia remains unclear. Here, we report the crystal and cryo-electron microscopy (EM) structures of a toxin effector duet comprising the domain of unknown function in the first position (DUF1)/Rho inactivation domain (RID) complexed with human targets. These structures reveal how the duet is used by bacteria as a potent weapon. The data show that DUF1 acts as a RID-dependent transforming NADase domain (RDTND) that disrupts NAD homeostasis by hijacking calmodulin. The cryo-EM structure of the RDTND-RID duet complexed with calmodulin and Rac1, together with immunological analyses in vitro and in mice, provide mechanistic insight into how V. vulnificus uses the duet to suppress ROS generation by depleting NAD(P) and modifying Rac1 in a mutually-reinforcing manner that ultimately paralyzes first line immune responses, promotes dissemination of invaders, and induces sepsis. These data may allow development of tools or strategies to combat MARTX toxin-related human diseases.
External linksNat Commun / PubMed:39043696 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.35 - 4.32 Å
Structure data

EMDB-37593: Vibrio vulnificus MARTX effector duet (RDTND-RID) complexed with human Rac1 Q61L and calmodulin
Method: EM (single particle) / Resolution: 4.32 Å

PDB-8k9z:
Crystal structure of Vibrio vulnificus RID-dependent transforming NADase domain (RDTND)/calmodulin-binding domain of Rho inactivation domain (RID-CBD) complexed with Ca2+-bound calmodulin
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

PDB-8ka0:
Crystal structure of Vibrio vulnificus RID-dependent transforming NADase domain (RDTND)/calmodulin-binding domain of Rho inactivation domain (RID-CBD) complexed with Ca2+-bound calmodulin and a nicotinamide adenine dinucleotide (NAD+)
Method: X-RAY DIFFRACTION / Resolution: 2.35 Å

PDB-8ka1:
Crystal structure of Vibrio vulnificus RID-dependent transforming NADase domain (RDTND)/calmodulin-binding domain of Rho inactivation domain (RID-CBD) complexed with Ca2+-free calmodulin
Method: X-RAY DIFFRACTION / Resolution: 2.82 Å

PDB-8ka2:
Crystal structure of the RID-dependent transforming NADase domain (RDTND)/calmodulin-binding domain of Rho inactivation domain (RID-CBD) from Vibrio vulnificus
Method: X-RAY DIFFRACTION / Resolution: 3.38 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-NAD:
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / NAD*YM

ChemComp-GOL:
GLYCEROL

ChemComp-MG:
Unknown entry

Source
  • vibrio vulnificus (bacteria)
  • homo sapiens (human)
KeywordsTOXIN / MARTX toxin / RDTND-RID / NADase / CaM / NAD+

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