The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures.
The human gene for catechol O-methyltransferase (COMT) contains a common polymorphism that results in substitution of methionine (M) for valine (V) at residue 108 of the soluble form of the protein. While the two proteins have similar kinetic properties, 108M COMT loses activity more rapidly than 108V COMT at 37 degrees C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 degrees C. The 108M allele has been associated with increased risk for breast cancer, obsessive-compulsive disorder, and aggressive and highly antisocial manifestations of schizophrenia. In the current work, we have constructed homology models for both human COMT polymorphs and performed molecular dynamics simulations of these models at 25, 37, and 50 degrees C to explore the structural consequences of the 108V/M polymorphism. The simulations indicated that replacing valine with the larger methionine residue led to greater solvent exposure of residue 108 and heightened packing interactions between M108 and helices alpha2, alpha4 (especially with R78), and alpha5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 A away, leading to a loosening of the active site. At physiological temperature, 108M COMT sampled a larger distribution of conformations than 108V. 108M COMT was more prone to active-site distortion and had greater overall, and SAM binding site, solvent accessibility than 108V COMT at 37 degrees C. Similar structural perturbations were observed in the 108V protein only at 50 degrees C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.
Department of Biochemistry, University of Washington, Seattle, Washington 98195-7610, USA.
Karen
K
Rutherford
Brian J
BJ
Bennion
William W
WW
Parson
Valerie
V
Daggett
D000595:Amino Acid Sequence; D002394:Catechol O-Methyltransferase / Q000737:chemistry* / Q000235:genetics*; D003198:Computer Simulation; D004795:Enzyme Stability; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D012436:S-Adenosylmethionine / Q000737:chemistry; D016415:Sequence Alignment; D013696:Temperature
D012436:S-Adenosylmethionine; D002394:Catechol O-Methyltransferase