A common polymorphism in the SFTPD gene influences assembly, function, and concentration of surfactant protein D.
Surfactant protein D (SP-D) plays important roles in the host defense against infectious microorganisms and in regulating the innate immune response to a variety of pathogen-associated molecular pattern. SP-D is mainly expressed by type II cells of the lung, but SP-D is generally found on epithelial surfaces and in serum. Genotyping for three single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met(11)Thr), 160 (Ala(160)Thr), and 270 (Ser(270)Thr) of the SP-D gene was performed and related to the SP-D levels in serum. Individuals with the Thr/Thr(11)-encoding genotype had significantly lower SP-D serum levels than individuals with the Met/Met(11) genotype. Gel filtration chromatography revealed two distinct m.w. peaks with SP-D immunoreactivity in serum from Met/Met(11)-encoding genotypes. In contrast, Thr/Thr(11) genotypes lacked the highest m.w. form. A similar SP-D size distribution was found for recombinant Met(11) and Thr(11) expressed in human embryonic kidney cells. Atomic force microscopy of purified SP-D showed that components eluting in the position of the high m.w. peak consist of multimers, dodecamers, and monomers of subunits, whereas the second peak exclusively contains monomers. SP-D from both peaks bound to mannan-coated ELISA plates. SP-D from the high m.w. peak bound preferentially to intact influenza A virus and Gram-positive and Gram-negative bacteria, whereas the monomeric species preferentially bound to isolated LPS. Our data strongly suggest that polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and the concentration of the molecule in serum.
Leth-Larsen
Rikke
R
Medical Biotechnology Center, Institute for Medical Biology, University of Southern Denmark, Odense, Denmark.
Garred
Peter
P
Jensenius
Henriette
H
Meschi
Joseph
J
Hartshorn
Kevan
K
Madsen
Jens
J
Tornoe
Ida
I
Madsen
Hans O
HO
Sørensen
Grith
G
Crouch
Erika
E
Holmskov
Uffe
U
D000483:Alleles; D000653:Amniotic Fluid / Q000737:chemistry / Q000378:metabolism; D001422:Bacterial Adhesion / Q000276:immunology; D002460:Cell Line; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006090:Gram-Negative Bacteria / Q000276:immunology / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D037663:Pulmonary Surfactant-Associated Protein D; D011994:Recombinant Proteins