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Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor.

Shen Y, Zhukovskaya NL, Guo Q, Florián J, Tang WJ
EMBO J 24 929-41 (2005)
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Cited: 87 times
EuropePMC logo PMID: 15719022

Abstract

Edema factor (EF), a key anthrax exotoxin, has an anthrax protective antigen-binding domain (PABD) and a calmodulin (CaM)-activated adenylyl cyclase domain. Here, we report the crystal structures of CaM-bound EF, revealing the architecture of EF PABD. CaM has N- and C-terminal domains and each domain can bind two calcium ions. Calcium binding induces the conformational change of CaM from closed to open. Structures of the EF-CaM complex show how EF locks the N-terminal domain of CaM into a closed conformation regardless of its calcium-loading state. This represents a mechanism of how CaM effector alters the calcium affinity of CaM and uncouples the conformational change of CaM from calcium loading. Furthermore, structures of EF-CaM complexed with nucleotides show that EF uses two-metal-ion catalysis, a prevalent mechanism in DNA and RNA polymerases. A histidine (H351) further facilitates the catalysis of EF by activating a water to deprotonate 3'OH of ATP. Mammalian adenylyl cyclases share no structural similarity with EF and they also use two-metal-ion catalysis, suggesting the catalytic mechanism-driven convergent evolution of two structurally diverse adenylyl cyclases.

Reviews - 1xfx mentioned but not cited (1)

  1. Molecular motions as a drug target: mechanistic simulations of anthrax toxin edema factor function led to the discovery of novel allosteric inhibitors. Laine E, Martínez L, Ladant D, Malliavin T, Blondel A. Toxins (Basel) 4 580-604 (2012)

Articles - 1xfx mentioned but not cited (6)

  1. Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor. Shen Y, Zhukovskaya NL, Guo Q, Florián J, Tang WJ. EMBO J. 24 929-941 (2005)
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