Structure of Key Enzyme in Plague Bacterium Found

Ribbon rendering of the structure of AC-IV in Yersina pestis as determined at NIST. The enzyme is a dimer (two identical subunits around a vertical axis), and each of the two subunits forms a central barrel made of eight strands surrounded by short helices. The active site is believed to lie inside the barrel.                       Credit: NISTView hi-res image

             

Researchers at the National Institute of Standards and  Technology (NIST) have solved the structure of a key enzyme from the bacterium  responsible for plague, finding that it has a highly unusual configuration. The  results may shed light both on how the bacterium kills and on fundamental cell  signaling processes.

             

The NIST team determined the three-dimensional shape of  class IV adenylyl cyclase (AC), an enzyme found in plague bacteria—Yersinia  pestis—by purifying and crystallizing the protein and using X-ray  crystallography at the Center for Advanced Research in Biotechnology to resolve  its configuration. Adenylyl cyclase is a fundamental enzyme found in one form  or another in organisms ranging from bacteria to mammals. It synthesizes cyclic  AMP (cAMP*), an important signaling molecule that in turn triggers a variety of  cellular processes. Six distinct classes of AC are known, playing a wide  variety of roles. AC-II is part of the anthrax bacterium’s killing mechanism,  for example, while AC-III triggers adrenaline release in humans.

             

Shape plays an essential role in determining the biological  function of a protein, but it’s very difficult to determine for such large  molecules. Three-dimensional structures are known for only two other forms of  AC. The NIST experiments revealed that AC-IV has a shape completely different  from the other two known shapes. AC-IV folds into a rare form of a barrel-like  shape previously seen in only three other unrelated proteins.

             

The purpose of AC-IV in plague is not well understood, but  it may play a role in disrupting cell processes in the infected host. Plague is  not as common as it was in the Middle Ages, when it killed millions, but the  World Health Organization still logs about 1,000 to 3,000 cases a year, an  average of 10 to 15 in the United    States. It is rated as a highest category  biothreat agent by the Centers for Disease Control and Prevention and the  National Institute of Allergy and Infectious Diseases. Fundamental molecular  data on this enzyme and its various forms may be critical to the development of  defenses against plague and other pathogens, including Bacillus anthracis (Anthrax) and Bordetella pertussis (Whooping cough). Beyond that,  structural and functional studies of AC-IV, with its unusual shape, may lead to  deeper understanding of the cAMP signaling mechanism and other fundamental  cellular processes.

             

Details of the structure of AC-IV are published in: D.T. Gallagher, N. Smith, S-K Kim, A. Heroux, H. Robinson  and P. Reddy. Structure of the class IV adenylyl cyclase reveals a novel fold. J. Mol. Biol., In Press, Corrected Proof, Available online 14 Aug. 2006.

             

*cyclic adenosine 3’, 5’- monophosphate