The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures

Karen Rutherford, Brian J. Bennion, William W. Parson, Valerie Daggett

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 °C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 °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 °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 α2, α4 (especially with R78), and α5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 Å 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 °C. Similar structural perturbations were observed in the 108V protein only at 50 °C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.

Original languageEnglish (US)
Pages (from-to)2178-2188
Number of pages11
JournalBiochemistry
Volume45
Issue number7
DOIs
StatePublished - Feb 21 2006
Externally publishedYes

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Catechol O-Methyltransferase
Polymorphism
Temperature
S-Adenosylmethionine
Catalytic Domain
Valine
Methionine
Proteins
Obsessive-Compulsive Disorder
Molecular Dynamics Simulation
Conformations
Molecular dynamics
Schizophrenia
Substitution reactions
Genes
Alleles
Binding Sites
Breast Neoplasms
Kinetics

ASJC Scopus subject areas

  • Biochemistry

Cite this

The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures. / Rutherford, Karen; Bennion, Brian J.; Parson, William W.; Daggett, Valerie.

In: Biochemistry, Vol. 45, No. 7, 21.02.2006, p. 2178-2188.

Research output: Contribution to journalArticle

Rutherford, Karen ; Bennion, Brian J. ; Parson, William W. ; Daggett, Valerie. / The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures. In: Biochemistry. 2006 ; Vol. 45, No. 7. pp. 2178-2188.
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abstract = "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 °C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 °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 °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 α2, α4 (especially with R78), and α5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 {\AA} 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 °C. Similar structural perturbations were observed in the 108V protein only at 50 °C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.",
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AB - 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 °C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 °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 °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 α2, α4 (especially with R78), and α5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 Å 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 °C. Similar structural perturbations were observed in the 108V protein only at 50 °C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.

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