Functional analysis of an ADAMTS10 signal peptide mutation in Weill-Marchesani syndrome demonstrates a long-range effect on secretion of the full-length enzyme
| Autor: | Valérie Cormier-Daire, Lauren W. Wang, Suneel S. Apte, Wendy E. Kutz, Elias I. Traboulsi, Nathalie Dagoneau, Kazimir J. Odrcic |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Signal peptide
DNA Mutational Analysis Biology Protein Sorting Signals Signal peptide processing Cell Line ADAMTS Proteins Chlorocebus aethiops Genetics Protein biosynthesis Missense mutation Animals Humans Protein precursor Genetics (clinical) Growth Disorders Aged 80 and over Signal peptidase Edman degradation Syndrome Protein Structure Tertiary ADAM Proteins Biochemistry COS Cells Mutation Protein folding |
| Zdroj: | Human mutation. 29(12) |
| ISSN: | 1098-1004 |
| Popis: | We report the identification and functional analysis of the first missense ADAMTS10 mutation (c.73G>A; p.Ala25Thr) causing recessive Weill-Marchesani syndrome (WMS). The Ala25 residue affected by the missense mutation is at the −1 position relative to the ADAMTS10 signal peptidase cleavage site. p.Ala25Thr substituted full-length ADAMTS10 showed consistent and significantly diminished secretion in both HEK293F and Cos-1 cells. However, a C-terminally truncated construct lacking the ancillary domain and containing only the signal peptide, the propeptide and the catalytic domain (p.Ala25Thr Pro-Cat) was efficiently secreted in both HEK293F cells and Cos-1 cells. Edman degradation of purified p.Ala25Thr Pro-Cat and p.Ala25Thr substituted full-length ADAMTS10 from HEK293F cells demonstrated correct signal peptide processing. Thus, the p.Ala25Thr substitution hinders secretion of full-length ADAMTS10, but not Pro-Cat from cells, yet permits signal peptide removal. We infer that folding of the complex C-terminal ancillary domain is the rate-limiting step in biosynthesis of ADAMTS10, and that it (but not Pro-Cat) is sensitive to subtle changes in efficiency of signal peptide cleavage. These observations represent an unprecedented effect of a signal peptide mutation and support a model in which the initial cotranslational processing events during protein biosynthesis can have long-range effects on protein folding and secretion. Hum Mutat 0, l–10, 2008. © 2008 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text