The polarity of the amino acid residue 118 of calcineurin B is closely linked to calcineurin enzyme activity.
Calcineurin(Cn), a multifunctional regulator expressed in several tissues and organs, consists of CnA (catalytic subunit) and CnB (regulatory subunit). The crystal structure shows that the hydrophobic groove formed by 118-123 residues of CnB is necessary for its interactions with two different immunosuppressant-immunophilin complexes and with CnA. In this report, we focus on Met118 of CnB to study the association between conformational states of CnB and the phosphatase activity of Cn. We found that hydrophobicity in the region around site118 of CnB is essential for the Cn activity. Polar mutants significantly weakened the enzymatic activity compared with the nonpolar ones. The data showed that some modest alterations in the vicinity of site118 impaired the integrality and compactness of hydrophobic microenvironment, and this might explain why CnB mutants defective in hydrophobicity failed in activating Cn. This requirement of hydrophobic microenvironment around site118 in CnB suggests that, besides the mutations in the catalytic subunit CnA, which impairs Cn phosphatase activity, and had been identified to be associated with diseases such as Alzheimer's disease (AD), the mutations in CnB might also affect Cn enzymatic activity in vivo, and this might be helpful for our further research on mechanisms of diseases associated with Cn.
Chen
Qing
Q
Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing, People's Republic of China.
Wu
Wu
W
Li
Jing
J
Wei
Qun
Q
D000595:Amino Acid Sequence; D019703:Calcineurin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008715:Methionine / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011487:Protein Conformation
D008715:Methionine; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases