ArticleThe Brichos domain of prosurfactant protein C can hold and fold a transmembrane segment |
| Hanna Johansson, Maria Eriksson, Kerstin Nordling, Jenny Presto, Jan Johansson * |
Department of Anatomy, Physiology and Biochemistry, SLU, The Biomedical Centre, 751 23 Uppsala, Sweden
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| email: Jan Johansson (jan.johansson@afb.slu.se) |
*Correspondence to Jan Johansson, Department of Anatomy, Physiology and Biochemistry, SLU, The Biomedical Centre, 751 23 Uppsala, Sweden
Funded by:
Swedish Research Council; Grant Number: 10371
Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning
| Brichos domain chaperone protein misfolding protein-peptide interactions membrane protein amyloid disease |
Prosurfactant protein C (proSP-C) is a 197-residue integral membrane protein, in which the C-terminal domain (CTC, positions 59-197) is localized in the endoplasmic reticulum (ER) lumen and contains a Brichos domain (positions 94-197). Mature SP-C corresponds largely to the transmembrane (TM) region of proSP-C. CTC binds to SP-C, provided that it is in nonhelical conformation, and can prevent formation of intracellular amyloid-like inclusions of proSP-C that harbor mutations linked to interstitial lung disease (ILD). Herein it is shown that expression of proSP-C (1-58), that is, the N-terminal propeptide and the TM region, in HEK293 cells results in virtually no detectable protein, while coexpression of CTC in trans yields SDS-soluble monomeric proSP-C (1-58). Recombinant human (rh) CTC binds to cellulose-bound peptides derived from the nonpolar TM region, but not the polar cytosolic part, of proSP-C, and requires  5-residues for maximal binding. Binding of rhCTC to a nonhelical peptide derived from SP-C results in  -helix formation provided that it contains a long TM segment. Finally, rhCTC and rhCTC Brichos domain shows very similar substrate specificities, but rhCTCL188Q, a mutation linked to ILD is unable to bind all peptides analyzed. These data indicate that the Brichos domain of proSP-C is a chaperone that induces -helix formation of an aggregation-prone TM region. |
Received: 28 January 2009; Revised: 16 March 2009; Accepted: 23 March 2009
10.1002/pro.123
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