2cb5

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HUMAN BLEOMYCIN HYDROLASE, C73S/DELE455 MUTANT

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known disease associated with this structure: Alzheimer disease, susceptibility to OMIM:[602403]

About this Structure

2CB5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Crystal structure of human bleomycin hydrolase, a self-compartmentalizing cysteine protease., O'Farrell PA, Gonzalez F, Zheng W, Johnston SA, Joshua-Tor L, Structure. 1999 Jun 15;7(6):619-27. PMID:10404591

Page seeded by OCA on Mon Nov 12 21:13:28 2007