Determination of encephalomyocarditis viral diabetogenicity by a putative binding site of the viral capsid protein.
The molecular mechanism by which some, but not all, variants of encephalomyocarditis (EMC) virus selectively infect pancreatic beta-cells in mice and induce IDDM has been an enigma for more than a decade. We report here that the binding site of the EMC viral capsid protein VP1 determines viral diabetogenicity. Recombinant chimeric EMC viruses containing threonine, serine, proline, aspartic acid, or valine at position 152 of the major capsid protein VP1 bind poorly to beta-cells. In contrast, recombinant chimeric EMC viruses containing alanine or glycine at position 152 of the VP1 bind efficiently to and infect beta-cells, resulting in the development of diabetes. Three-dimensional molecular modeling reveals that the van der Waals interactions are greater and the residues surrounding position 152 of the VP1 are more closely packed in recombinant chimeric viruses containing threonine, serine, proline, aspartic acid, or valine at position 152 than in recombinant chimeric viruses containing alanine or glycine at the same position. Our studies reveal that the surface areas surrounding alanine or glycine at position 152 of the VP1 are more accessible, thus increasing the availability of the binding sites for attachment to beta-cell receptors and resulting in viral infection and the development of diabetes.
Jun
H S
HS
Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases, Faculty of Medicine, the University of Calgary, Alberta, Canada.
Kang
Y
Y
Yoon
H S
HS
Kim
K H
KH
Notkins
A L
AL
Yoon
J W
JW
D000818:Animals; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D036022:Capsid Proteins; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000821:virology*; D004686:Encephalomyocarditis virus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D007515:Islets of Langerhans / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D017354:Point Mutation; D011487:Protein Conformation; D011995:Recombination, Genetic
D036022:Capsid Proteins; C096256:VP1 protein, encephalomyocarditis virus