A human skeletal overgrowth mutation increases maximal velocity and blocks desensitization of guanylyl cyclase-B.

[achondroplasia]

C-type natriuretic peptide (CNP ) increases long bone growth by stimulating guanylyl cyclase (GC )-B /NPR-B /NPR 2 . Recently , a Val to Met missense mutation at position 883 in the catalytic domain of GC -B was identified in humans with increased blood cGMP levels that cause abnormally long bones . Here , we determined how this mutation activates GC -B . In the absence of CNP , cGMP levels in cells expressing V 88 3 M -GC -B were increased more than 20 fold compared to cells expressing wild-type (WT )-GC -B , and the addition of CNP only further increased cGMP levels 2 -fold . In the absence of CNP , maximal enzymatic activity (Vmax ) of V 88 3 M -GC -B was increased 15 -fold compared to WT-GC -B but the affinity of the enzymes for substrate as revealed by the Michaelis constant (Km ) was unaffected . Surprisingly , CNP decreased the Km of V 88 3 M -GC -B 10 -fold in a concentration-dependent manner without increasing Vmax . Unlike the WT enzyme the Km reduction of V 88 3 M -GC -B did not require ATP . Unexpectedly , V 88 3 M -GC -B , but not WT-GC -B , failed to inactivate with time . Phosphorylation elevated but was not required for the activity increase associated with the mutation because the Val to Met substitution also activated a GC -B mutant lacking all known phosphorylation sites . We conclude that the V 88 3 M mutation increases maximal velocity in the absence of CNP , eliminates the requirement for ATP in the CNP -dependent Km reduction , and disrupts the normal inactivation process .

Diseases
Validation

Diseases presenting "long bone growth" symptom

achondroplasia

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