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Title: Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae

Mycoplasma pneumoniae (Mp) infections cause tracheobronchitis and “walking” pneumonia, and are linked to asthma and other reactive airway diseases. As part of the infectious process, the bacterium expresses a 591-aa virulence factor with both mono-ADP ribosyltransferase (mART) and vacuolating activities known as Community-Acquired Respiratory Distress Syndrome Toxin (CARDS TX). CARDS TX binds to human surfactant protein A and annexin A2 on airway epithelial cells and is internalized, leading to a range of pathogenetic events. In this paper, we present the structure of CARDS TX, a triangular molecule in which N-terminal mART and C-terminal tandem β-trefoil domains associate to form an overall architecture distinct from other well-recognized ADP-ribosylating bacterial toxins. We demonstrate that CARDS TX binds phosphatidylcholine and sphingomyelin specifically over other membrane lipids, and that cell surface binding and internalization activities are housed within the C-terminal β-trefoil domain. Finally, the results enhance our understanding of Mp pathogenicity and suggest a novel avenue for the development of therapies to treat Mp-associated asthma and other acute and chronic airway diseases.
Authors:
 [1] ;  [2] ;  [3] ; ORCiD logo [4] ;  [1] ;  [2] ;  [5] ;  [1] ;  [2] ;  [6]
  1. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry
  2. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Microbiology and Immunology. Center for Airway Inflammation Research
  3. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry. X-Ray Crystallography Core Lab.
  4. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry; Old Dominion Univ., Norfolk, VA (United States). Frank Reidy Center for Bioelectrics
  5. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry; St. Mary's Univ., San Antonio, TX (United States). Dept. of Biological Sciences
  6. Univ. of Texas Health Science Center, San Antonio, TX (United States). Dept. of Biochemistry. X-Ray Crystallography Core Lab.; US Dept. of Veterans Affairs, San Antonio, TX (United States). South Texas Veterans Health Care System
Publication Date:
OSTI Identifier:
1178475
Grant/Contract Number:
AC02-06CH11357; U19 AI070412; AQ-1399; P41 GM103403; P30 CA054174
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 112; Journal Issue: 16; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Univ. of Texas Health Science Center, San Antonio, TX (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH) (United States); Kleberg Foundation (United States); R. A. Welch Foundation (United States)
Contributing Orgs:
Old Dominion Univ., Norfolk, VA (United States); St. Mary's Univ., San Antonio, TX (United States); US Dept. of Veterans Affairs, San Antonio, TX (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; mycoplasma cytotoxin; single-crystal X-ray diffraction; ADP-ribosyltransferase; vacuolation; reactive airway disease