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Silencing of Aberrant Secretory Protein Expression by Disease-Associated Mutations
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
Number of Authors: 42019 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 431, no 14, p. 2567-2580Article in journal (Refereed) Published
Abstract [en]

Signal recognition particle (SRP) recognizes signal sequences of secretory proteins and targets them to the endoplasmic reticulum membrane for translocation. Many human diseases are connected with defects in signal sequences. The current dogma states that the molecular basis of the disease-associated mutations in the secretory proteins is connected with defects in their transport. Here, we demonstrate for several secretory proteins with disease-associated mutations that the molecular mechanism is different from the dogma. Positively charged or helix-breaking mutations in the signal sequence hydrophobic core prevent synthesis of the aberrant proteins and lead to degradation of their mRNAs. The degree of mRNA depletion depends on the location and severity of the mutation in the signal sequence and correlates with inhibition of SRP interaction. Thus, SRP protects secretory protein mRNAs from degradation. The data demonstrate that if disease-associated mutations obstruct SRP interaction, they lead to silencing of the mutated protein expression.

Place, publisher, year, edition, pages
2019. Vol. 431, no 14, p. 2567-2580
Keywords [en]
protein synthesis and transport, signal sequence, signal recognition particle (SRP), protein quality control, translational control
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-172028DOI: 10.1016/j.jmb.2019.05.011ISI: 000474681400008PubMedID: 31100385OAI: oai:DiVA.org:su-172028DiVA, id: diva2:1346334
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-27Bibliographically approved

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