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Effect of glycosylation of cyclooxygenase‐2 (COX‐2) on homodimerization
Author(s) -
VannVictorino Daniel DeWayne Colbert,
Cunanan Jelaine,
Chen Mindy,
Chan Rena,
Hall Randall W.,
Sevigny Mary B.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb79
Subject(s) - chemistry , cyclooxygenase , arachidonic acid , glycosylation , prostaglandin , biochemistry , dimer , biophysics , stereochemistry , enzyme , biology , organic chemistry
Prostaglandins are a group of fatty acid cell signals made from arachidonic acid. The prostaglandins have many roles in the body including inflammation response, contraction and relaxation of smooth muscle cells, vasodilation, and platelet aggregation. Cyclooxygenase‐2 (COX‐2) catalyzes two steps in the prostaglandin pathway, wherein arachidonic acid is converted into prostaglandin G 2 which is then converted into prostaglandin H 2 . Though COX‐2 is best known for its role in the inflammatory response, overexpression of COX‐2 plays a role in various diseases such as arthritis and certain cancers. COX‐2 exists as two glycoforms—72 and 74kDa— due to a variable glycosylation site at Asn 580 . Our lab has previously reported that this variable glycosylation affects the turnover rate of the COX‐2 protein and reduces the efficacy of several COX‐2 inhibitors. In this current study, we wish to determine the effect of this glycosylation on COX‐2 dimerization, since COX‐2 activity depends on dimerization. The molecular dynamics computer program NAMD was used to determine the difference in dimerization free energies between the 74kDa/74kDa COX‐2, the 72kDa/74kDa COX‐2, and the 72kDa/72kDa COX‐2 dimers to elucidate the influence of variable glycosylation on dimerization. The results indicate that the Gibbs free energy of dimerization for the 72kDa/74kDa dimer is more negative than the corresponding Gibbs free energy of dimerization for the 74kDa/74kDa dimer. These data indicate that dimerization between the 72kDa and the 74kDa COX‐2 monomers is more energetically favorable than dimerization between two 74kDa monomers. Further computational studies analyzing the DG of the 72kDa/72kDa dimer are currently being carried out, and future studies will include immunoprecipitation experiments to confirm these computer simulation results.