O'Farrell, P. A., Gonzalez, F., Zheng, W., Johnston, S. A., Joshua-Tor, L. (June 1999) Crystal structure of human bleomycin hydrolase, a self-compartmentalizing cysteine protease. Structure, 7 (6). pp. 619-27. ISSN 0969-2126 (Public Dataset)
Abstract
BACKGROUND: Bleomycin hydrolase (BH) is a cysteine protease that is found in all tissues in mammals as well as in many other eukaryotes and prokaryotes. Although its conserved cellular function is as yet unknown, human bleomycin hydrolase (hBH) has clinical significance in that it is thought to be the major cause of tumor cell resistance to bleomycin chemotherapy. In addition, it has been reported that an allelic variant of hBH is genetically linked to Alzheimer's disease. RESULTS: We have determined the crystal structures of wild-type hBH and of a mutant form of the enzyme. The overall structure is very similar to that of the previously determined yeast homolog, however, there is a striking difference in the charge distribution. The central channel, which has a strong positive electrostatic potential in the yeast protein, is slightly negative in hBH. We have determined that hBH does not have the DNA-binding activity of the yeast protein and that the enzyme is localized to the cytoplasm. CONCLUSIONS: The difference in charge distribution between the yeast and human BH enzymes is most likely responsible for the difference in DNA-binding activity. Nevertheless, the C-terminal autoprocessing activity and the role of the C terminus as a determinant for peptidase activity are conserved between the yeast and human forms. The structure of hBH suggests that the putative Alzheimer's disease linked variation does not directly alter the intrinsic peptidase activity. Rather, the position of the mutation suggests that it could affect interactions with another protein, which may modulate peptidase activity through repositioning of the C terminus.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Alzheimer Disease enzymology Amino Acid Sequence Antineoplastic Agents metabolism therapeutic use Binding Sites Bleomycin metabolism therapeutic use Crystallography X-Ray Cysteine Endopeptidases chemistry genetics DNA-Binding Proteins chemistry Drug Resistance Electrostatics Fluorescent Antibody Technique Fungal Proteins chemistry Humans Hydrogen Bonding Models, Molecular Molecular Sequence Data Mutation genetics Protein Conformation Recombinant Proteins chemistry |
| Subjects: | Investigative techniques and equipment > X-Ray Diffraction bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein structure rendering Investigative techniques and equipment > x ray crystallography |
| CSHL Authors: | |
| Communities: | CSHL labs > Joshua-Tor lab |
| Depositing User: | CSHL Librarian |
| Date: | 15 June 1999 |
| Date Deposited: | 20 Mar 2012 20:43 |
| Last Modified: | 05 Sep 2017 20:42 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/25499 |
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