DMCA
RESEARCH ARTICLE Human Mutation OFFICIAL JOURNAL Cystathionine b-Synthase Mutations: Effect of Mutation Topology on Folding and Activity www.hgvs.org (2010)
BibTeX
@MISC{Sokolová10researcharticle,
author = {Jitka Sokolová and Veronika Klatovská and Jakub Krijt and Karel Jelínek and Jan P. Kraus and Communicated David and N. Cooper},
title = {RESEARCH ARTICLE Human Mutation OFFICIAL JOURNAL Cystathionine b-Synthase Mutations: Effect of Mutation Topology on Folding and Activity www.hgvs.org},
year = {2010}
}
Share
 |
 |
 |
 |
||
OpenURL
Abstract
ABSTRACT: Misfolding of mutant enzymes may play an important role in the pathogenesis of cystathionine b-synthase (CBS) deficiency. We examined properties of a series of 27 mutant variants, which together represent 70 % of known alleles observed in patients with homocystinuria due to CBS deficiency. The median amount of SDS-soluble mutant CBS polypeptides in the pellet after centrifugation of bacterial extracts was increased by 50 % compared to the wild type. Moreover, mutants formed on average only 12 % of tetramers and their median activity reached only 3 % of the wild-type enzyme. In contrast to the wild-type CBS about half of mutants were not activated by S-adenosylmethionine. Expression at 181C substantially increased the activity of five mutants in parallel with increasing the amounts of tetramers. We further analyzed the role of solvent accessibility of mutants as a determinant of their folding and activity. Buried mutations formed on average less tetramers and exhibited 23 times lower activity than the solvent exposed mutations. In summary, our results show that topology of mutations predicts in part the behavior of mutant CBS, and that misfolding may be an important and frequent pathogenic mechanism in CBS deficiency.
Keyphrases
mutation topology cbs deficiency important role mutant cbs median activity mutant variant frequent pathogenic mechanism sds-soluble mutant cbs polypeptide mutant enzyme wild-type enzyme wild type cystathionine b-synthase mutation predicts bacterial extract solvent accessibility wild-type cbs median amount
