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J. Biol. Chem., Vol. 281, Issue 30, 21032-21039, July 28, 2006

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The Brichos Domain-containing C-terminal Part of Pro-surfactant Protein C Binds to an Unfolded Poly-Val Transmembrane Segment^*

Hanna Johansson, Kerstin Nordling, Timothy E. Weaver, and Jan Johansson¹

From the Department of Molecular Biosciences, Swedish University of Agricultural Sciences, The Biomedical Centre, S-751 23 Uppsala, Sweden and the Division of Pulmonary Biology, Cincinnati Children's Research Foundation, Cincinnati, Ohio 45229-3039

Native lung surfactant protein C (SP-C) is a 4.2-kDa acylpeptide that associates with alveolar surfactant phospholipids via a transmembrane -helix. This helix contains mainly Val, although poly-Val is inefficient in helix formation, and helical SP-C can spontaneously convert to -sheet aggregates and amyloid-like fibrils. SP-C is cleaved out from a 21-kDa integral membrane protein, proSP-C, in the alveolar type II cell. Recently several mutations localized in the endoplasmic reticulum-lumenal (C-terminal) part of proSP-C (CTproSP-C) have been associated with intracellular accumulation of toxic forms of proSP-C, low levels of mature SP-C, and development of interstitial lung disease. CTproSP-C contains a 100-residue Brichos domain of unknown function that is also found in other membrane proteins associated with amyloid formation, dementia, and cancer. Here we find that recombinant CTproSP-C binds lipid-associated SP-C, which is in -strand conformation, and that this interaction results in an increased helical content. In contrast, CTproSP-C does not bind -helical SP-C. Recombinant CTproSP-C(L188Q), a mutation associated with interstitial lung disease, shows secondary and quaternary structures similar to those of wild type CTproSP-C but is unable to bind lipid-associated -strand SP-C. Transfection of CTproSP-C into HEK293 cells that express proSP-C(L188Q) increases the amount of proSP-C protein, whereas no effect is seen on cells expressing wild type proSP-C. These findings suggest that CTproSP-C binds nonhelical SP-C and thereby prevents -sheet aggregation and that mutations in CTproSP-C can interfere with this function.

Received for publication, March 30, 2006 , and in revised form, May 11, 2006.

^* This work was supported by Swedish Research Council Project 10371 and by the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Biosciences, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, S-751 23 Uppsala, Sweden. Tel.: 46-18-4714065; Fax: 46-18-550762; E-mail: jan.johansson{at}vmk.slu.se.

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