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Title | Structural basis for non-canonical integrin engagement by Bordetella adenylate cyclase toxin. |
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Journal, issue, pages | Cell Rep, Vol. 40, Issue 7, Page 111196, Year 2022 |
Publish date | Aug 16, 2022 |
Authors | Jory A Goldsmith / Andrea M DiVenere / Jennifer A Maynard / Jason S McLellan / |
PubMed Abstract | Integrins are ubiquitous cell-surface heterodimers that are exploited by pathogens and toxins, including leukotoxins that target β integrins on phagocytes. The Bordetella adenylate cyclase toxin ...Integrins are ubiquitous cell-surface heterodimers that are exploited by pathogens and toxins, including leukotoxins that target β integrins on phagocytes. The Bordetella adenylate cyclase toxin (ACT) uses the αβ integrin as a receptor, but the structural basis for integrin binding and neutralization by antibodies is poorly understood. Here, we use cryoelectron microscopy to determine a 2.7 Å resolution structure of an ACT fragment bound to αβ. This structure reveals that ACT interacts with the headpiece and calf-2 of the α subunit in a non-canonical manner specific to bent, inactive αβ. Neutralizing antibody epitopes map to ACT residues involved in α binding, providing the basis for antibody-mediated attachment inhibition. Furthermore, binding to αβ positions the essential ACT acylation sites, which are conserved among toxins exported by type I secretion systems, at the cell membrane. These findings reveal a structural mechanism for integrin-mediated attachment and explain antibody-mediated neutralization of ACT intoxication. |
External links | Cell Rep / PubMed:35977491 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.7 - 3.1 Å |
Structure data | EMDB-26738, PDB-7usl: EMDB-26739, PDB-7usm: EMDB-27122: Global refinement for integrin alphaM/beta2 ectodomain in complex with adenylate cyclase toxin RTX751 and M1F5 Fab EMDB-27123: Tailpiece local refinement for integrin alphaM/beta2 ectodomain in complex with adenylate cyclase toxin RTX751 and M1F5 Fab EMDB-27124: Acylation domain local refinement for integrin alphaM/beta2 ectodomain in complex with adenylate cyclase toxin RTX751 and M1F5 Fab EMDB-27125: Global refinement for integrin alphaM/beta2 ectodomain EMDB-27126: Tailpiece local refinement for integrin alphaM/beta2 ectodomain |
Chemicals | ChemComp-CA: ChemComp-NAG: |
Source |
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Keywords | TOXIN / Receptor / Complex / Integrin / CELL ADHESION / Complement |