The Brichos domain of prosurfactant protein C can hold and fold a transmembrane segment

Willander, HannaSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för anatomi, fysiologi och biokemi,Department of Anatomy, Physiology and Biochemistry (AFB) (författare)

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.

Nordling, KerstinSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för anatomi, fysiologi och biokemi,Department of Anatomy, Physiology and Biochemistry (AFB)(Swepub:slu)48936 (författare)
Presto, JennySwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för anatomi, fysiologi och biokemi,Department of Anatomy, Physiology and Biochemistry (AFB)(Swepub:slu)52706 (författare)
Johansson, JanSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för anatomi, fysiologi och biokemi,Department of Anatomy, Physiology and Biochemistry (AFB)(Swepub:slu)47966 (författare)
Sveriges lantbruksuniversitetInstitutionen för anatomi, fysiologi och biokemi (creator_code:org_t)
Sveriges lantbruksuniversitet

Av författaren/redakt...: Willander, Hanna; Nordling, Kersti ...; Presto, Jenny; Johansson, Jan

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