Silencing of Aberrant Secretory Protein Expression by Disease-Associated Mutations |
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| Affiliation: | 1. Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA;2. Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA;3. Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden;4. Sweden and Science for Life Laboratory Stockholm University, SE-171 21 Solna, Sweden;1. Department of Pathology and Lab Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;2. Department of Biology, Drexel University, Philadelphia, PA 19104, USA;1. Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden;2. Science for Life Laboratory, Stockholm University, Box 1031, SE-171 21 Solna, Sweden;1. Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden;2. Centre for Biomimetic Sensor Science, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Drive, 637553, Singapore;1. Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden;2. Science for Life Laboratory, Stockholm University, SE-17177 Solna, Sweden;1. Center for Biomembrane Research, Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden;2. Institute of Physical and Theoretical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Straße 7, D-60438 Frankfurt am Main, Germany;3. Science for Life Laboratory, Stockholm University, SE-17177 Solna, Sweden |
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| Abstract: | 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. |
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