期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 28, 页码 17628-17641出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.630343
关键词
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资金
- Spanish Ministry of Economy and Competitiveness [SAF2012-32728]
- Institute of Health Carlos III (ISCiii) (Spanish Research Center of Respiratory Diseases) [CIBERES CB06/06/0002]
- Swedish Research Council
- Henrik Granholms Stiftelse [SU 33-1013-09]
- Swedish Cancer Society [13624]
- Swedish Foundation for International Cooperation in Research and Higher Education (STINT) [210/083(12), KU 2003-4674]
- Swedish Foundation for Strategic Research [A305:200]
- Swedish Alzheimer foundation
- Ake Wibergs foundation
- Magn Bergvalls foundation
- Foundation of Gamla tjanarinnor
- Loo and Hans Ostermans foundation for geriatric research
Surfactant protein C (SP-C) is a novel amyloid protein found in the lung tissue of patients suffering from interstitial lung disease (ILD) due to mutations in the gene of the precursor protein pro-SP-C. SP-C is a small alpha-helical hydrophobic protein with an unusually high content of valine residues. SP-C is prone to convert into beta-sheet aggregates, forming amyloid fibrils. Nature's way of solving this folding problem is to include a BRICHOS domain in pro-SP-C, which functions as a chaperone for SP-C during biosynthesis. Mutations in the pro-SP-C BRICHOS domain or linker region lead to amyloid formation of the SP-C protein and ILD. In this study, we used an in vitro transcription/translation system to study translocon-mediated folding of the WT pro-SP-C poly-Val and a designed poly-Leu transmembrane (TM) segment in the endoplasmic reticulum (ER) membrane. Furthermore, to understand how the pro-SP-C BRICHOS domain present in the ER lumen can interact with the TM segment of pro-SP-C, we studied the membrane insertion properties of the recombinant form of the pro-SP-C BRICHOS domain and two ILD-associated mutants. The results show that the co-translational folding of the WT pro-SP-C TM segment is inefficient, that the BRICHOS domain inserts into superficial parts of fluid membranes, and that BRICHOS membrane insertion is promoted by poly-Val peptides present in the membrane. In contrast, one BRICHOS and one non-BRICHOS ILD-associated mutant could not insert into membranes. These findings support a chaperone function of the BRICHOS domain, possibly together with the linker region, during pro-SP-C biosynthesis in the ER.
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