N-terminally extended surfactant protein (SP) C isolated from SP-B-deficient children has reduced surface activity and inhibited lipopolysaccharide binding.
In both humans and mice, a deficiency of surfactant protein B (SP-B) is associated with a decreased concentration of mature SP-C and accumulation of a larger SP-C peptide, denoted SP-C(i), which is not observed under normal conditions. Isolation of hydrophobic polypeptides from the lungs of children who died with two different SP-B mutations yielded pure SP-C(i) and showed only trace amounts of mature SP-C. Determination of the SP-C(i) covalent structure revealed a 12-residue N-terminal peptide segment, followed by a 35-residue segment that is identical to mature SP-C. The SP-C(i) structure determined herein is similar to that of a proposed late intermediate in the processing of proSP-C, suggesting that SP-C(i) is the immediate precursor of SP-C. In bronchoalveolar lavage fluid from transgenic mice with a focal deficiency of SP-B, SP-C(i) was detected in the biophysically active, large aggregate fraction and was associated with membrane structures that are typical for a large aggregate surfactant. However, unlike SP-C, SP-C(i) exhibited a very poor ability to promote phospholipid adsorption, gave high surface tension during cyclic film compression, and did not bind lipopolysaccharide in vitro. SP-C(i) is thus capable of associating with surfactant lipids, but its N-terminal dodecapeptide segment must be proteolytically removed to generate a biologically functional peptide. The results of this study indicate that the early postnatal fatal respiratory distress seen in SP-B-deficient children is combined with the near absence of active variants of SP-C.
Li
Jing
J
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Ikegami
Machiko
M
Na
Cheng-Lun
CL
Hamvas
Aaron
A
Espinassous
Quentin
Q
Chaby
Richard
R
Nogee
Lawrence M
LM
Weaver
Timothy E
TE
Johansson
Jan
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002648:Child; D002851:Chromatography, High Pressure Liquid; D006720:Homozygote; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008168:Lung / Q000737:chemistry; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000302:isolation & purification / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D037701:Pulmonary Surfactant-Associated Protein B / Q000172:deficiency* / Q000235:genetics*; D037721:Pulmonary Surfactant-Associated Protein C / Q000302:isolation & purification* / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013499:Surface Properties; D013552:Swine
D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011498:Protein Precursors; D037701:Pulmonary Surfactant-Associated Protein B; D037721:Pulmonary Surfactant-Associated Protein C