Sáenz, AlejandraPresto. JennyLara, PatriciaAkinyi-Oloo, LauraGarcía-Fojeda García-Valdecasas, María BelénNilsson, IngMarieJohansson, JanCasals Carro, María Cristina2024-01-222024-01-222015Sáenz A, Presto J, Lara P, Akinyi-Oloo L, García-Fojeda B, Nilsson I, Johansson J, Casals C. Folding and Intramembraneous BRICHOS Binding of the Prosurfactant Protein C Transmembrane Segment. J Biol Chem. 2015 Jul 10;290(28):17628-41. doi: 10.1074/jbc.M114.630343.0021-925810.1074/jbc.m114.630343https://hdl.handle.net/20.500.14352/94518Surfactant 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 α-helical hydrophobic protein with an unusually high content of valine residues. SP-C is prone to convert into β-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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.1074/jbc.m114.630343https://pubmed.ncbi.nlm.nih.gov/26041777/open access577.1Amyloid diseasesAmyloid-like fibrilChaperone activityLipid bilayerLipid-binding proteinLipid-protein interactionsLungMembrane structureProtein foldingPulmonary surfactantBioquímica (Biología)2403 Bioquímica