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Sammanfattning

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 a-helix formation provided that it contains a long TM segment. Finally, rhCTC and rhCTC Brichos domain shows very similar substrate specificities, but rhCTC(L188Q), 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 alpha-helix formation of an aggregation-prone TM region.

Nyckelord

Brichos domain; chaperone; protein misfolding; protein-peptide interactions; membrane protein; amyloid disease

Publicerad i

Protein Science
2009, volym: 18, nummer: 6, sidor: 1175-1182
Utgivare: JOHN WILEY & SONS INC

SLU författare

UKÄ forskningsämne

Molekylärbiologi
Biokemi

Publikationens identifierare

  • DOI: https://doi.org/10.1002/pro.123

Permanent länk till denna sida (URI)

https://res.slu.se/id/publ/49679