The crystal structure of human procathepsin K

Cathepsin K is a cysteine protease present in human osteoclasts that plays an important role in bone resorption, Cathepsin K is synthesized as an inac tive proenzyme and activated under conditions of low pH. Autoproteolytic pr ocessing of the N-terminal 99 amino acid propeptide produces the active, ma ture form of cathepsin K. It is presumed that the activation of procathepsi n K in vivo occurs in the bone resorption pit, which has a low-pH environme nt, We have determined the structure of human procathepsin K at 2.8 Angstro m resolution. The structure of the mature enzyme domain within procathepsin K is virtually identical to that of mature cathepsin K. The fold of the pr opeptide of procathepsin K is similar to that observed in procathepsins B a nd L despite differences in length and sequence. A portion of the propeptid e occupies the active site cleft of cathepsin K. Hydrophobic interactions, salt bridges, and hydrogen-bonding interactions are observed in the structu re of the propeptide and between the propeptide and the mature enzyme of pr ocathepsin K. These interactions suggest an explanation for the stability o f the proenzyme. The structure of procathepsin K contributes to an understa nding of the molecular basis of inhibition by the propeptide portion of the molecule and activation of this important member of the cysteine protease family.