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Crystal Structure of the Anthrax Toxin Protective Antigen Heptameric Prepore bound to the VWA domain of CMG2, an anthrax toxin receptorCrystal Structure of the Anthrax Toxin Protective Antigen Heptameric Prepore bound to the VWA domain of CMG2, an anthrax toxin receptor
Structural highlights
Disease[ANTR2_HUMAN] Defects in ANTXR2 are the cause of infantile systemic hyalinosis (ISH) [MIM:236490]. This autosomal recessive syndrome is similar to JHF, but has an earlier onset and a more severe course. Symptoms appear at birth or within the first months of life, with painful, swollen joint contractures, osteopenia, osteoporosis and livid red hyperpigmentation over bony prominences. Patients develop multiple subcutaneous skin tumors and gingival hypertrophy. Hyaline deposits in multiple organs, recurrent infections and intractable diarrhea often lead to death within the first 2 years of life. Surviving children may suffer from severely reduced mobility due to joint contractures.[1] [2] Defects in ANTXR2 are the cause of juvenile hyaline fibromatosis (JHF) [MIM:228600]. JHF is an autosomal recessive syndrome that is similar to ISH but takes a milder course. It is characterized by hyaline deposition in the dermis, multiple subcutaneous skin tumors and gingival hypertrophy, followed by progressive joint contractions, osteopenia and osteoporosis that may lead to a severe limitation of mobility.[3] [4] Function[PAG_BACAN] One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. PA binds to a receptor (ATR) in sensitive eukaryotic cells, thereby facilitating the translocation of the enzymatic toxin components, edema factor and lethal factor, across the target cell membrane. PA associated with LF causes death when injected, PA associated with EF produces edema. PA induces immunity to infection with anthrax. [ANTR2_HUMAN] Necessary for cellular interactions with laminin and the extracellular matrix.[5] [6] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAfter binding to cellular receptors and proteolytic activation, the protective antigen component of anthrax toxin forms a heptameric prepore. The prepore later undergoes pH-dependent conversion to a pore, mediating translocation of the edema and lethal factors to the cytosol. We describe structures of the prepore (3.6 A) and a prepore:receptor complex (4.3 A) that reveal the location of pore-forming loops and an unexpected interaction of the receptor with the pore-forming domain. Lower pH is required for prepore-to-pore conversion in the presence of the receptor, indicating that this interaction regulates pH-dependent pore formation. We present an example of a receptor negatively regulating pH-dependent membrane insertion. Structure of heptameric protective antigen bound to an anthrax toxin receptor: a role for receptor in pH-dependent pore formation.,Lacy DB, Wigelsworth DJ, Melnyk RA, Harrison SC, Collier RJ Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13147-51. Epub 2004 Aug 23. PMID:15326297[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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