title: Structure of CARDS toxin, a unique ADP-ribosylating and vacuolating cytotoxin from Mycoplasma pneumoniae.
abstract: 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. Here 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. 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.affiliation: Department of Biochemistry.
authors.forename: Argentina
authors.initials: A
authors.lastname: Becker
authors.affiliation: Department of Microbiology and Immunology/Center for Airway Inflammation Research, and.
authors.forename: T R
authors.initials: TR
authors.lastname: Kannan
authors.affiliation: Department of Biochemistry, X-Ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Taylor
authors.affiliation: Department of Biochemistry, Frank Reidy Center for Bioelectrics, Old Dominion University, Norfolk, VA 23508;
authors.forename: Olga N
authors.identifier: http://orcid.org/0000-0003-4950-4130
authors.initials: ON
authors.lastname: Pakhomova
authors.affiliation: Department of Biochemistry.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology/Center for Airway Inflammation Research, and.
authors.forename: Sudha R
authors.initials: SR
authors.lastname: Somarajan
authors.affiliation: Department of Biochemistry, Department of Biological Sciences, St. Mary's University, San Antonio, TX 78228; and.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Galaleldeen
authors.affiliation: Department of Biochemistry.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Holloway
authors.affiliation: Department of Microbiology and Immunology/Center for Airway Inflammation Research, and baseman@uthscsa.edu pjh@biochem.uthscsa.edu.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Baseman
authors.affiliation: Department of Biochemistry, X-Ray Crystallography Core Laboratory, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; South Texas Veterans Health Care System, US Department of Veterans Affairs, San Antonio, TX 78229 baseman@uthscsa.edu pjh@biochem.uthscsa.edu.
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D036002:ADP Ribose Transferases / Q000737:chemistry / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D003603:Cytotoxins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009177:Mycoplasma pneumoniae / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013109:Sphingomyelins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014617:Vacuoles / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; C546120:CARDS toxin, Mycoplasma pneumoniae; D003603:Cytotoxins; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D000246:Adenosine Diphosphate Ribose; D015060:1,2-Dipalmitoylphosphatidylcholine; D036002:ADP Ribose Transferases
keywords: ADP-ribosyltransferase; mycoplasma cytotoxin; reactive airway disease; single-crystal X-ray diffraction; vacuolation
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