Crystal structures of human procathepsin H

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Cathepsin H is a lysosomal cysteine protease involved in cancer and other diseases.
• It functions as an aminopeptidase, unique within its protease family.
• Procathepsin H, the inactive precursor, has poorly understood inhibition and activation mechanisms.

Purpose of the Study:

• To elucidate the structural and functional basis of procathepsin H inhibition and activation.
• To provide detailed structural information on human procathepsin H.

Main Methods:

• X-ray crystallography was used to determine the structures of human procathepsin H.
• Structures were resolved at 2.00 Å and 1.66 Å resolutions.
• Comparative structural analysis with mature cathepsin H and functional assays were performed.

Main Results:

• The crystal structures reveal the molecular basis for prodomain-mediated inhibition of the mature domain.
• The structures illustrate the reorientation of the mini-chain during activation.
• Procathepsin H was found to be trans-activated by cathepsin L, not auto-activated.

Conclusions:

• The determined structures offer detailed insights into procathepsin H inhibition and activation.
• Understanding these mechanisms is crucial for its role in disease pathologies.
• Trans-activation by cathepsin L is a key step in procathepsin H functionalization.