ReviewSurfactant proteins SP-A and SP-D: Structure, function and receptors
Introduction
Pulmonary surfactant is a complex mixture of lipids (90%) and proteins (5–10%) that constitutes the mobile liquid phase covering the large surface area of the alveolar epithelium. It maintains minimal surface tension within the lungs in order to avoid lung collapse during respiration. Surfactant is synthesized by alveolar type II cells and stored as intracellular inclusion organelles called ‘lamellar bodies’. It is then secreted into the alveolar space so as to form a lattice called ‘tubular myelin’, which is considered to be an intermediate product that forms the monolayer lipid film covering the alveolar space (Haagsman and van Golde, 1991, Wright and Dobbs, 1991). Dipalmitoylphosphatidylcholine (DPPC) is the major lipid component of surfactant, about 90% of which is phospholipid.
Four surfactant proteins (SP), SP-A, SP-B, SP-C and SP-D, are intimately associated with surfactant lipids in the lung and have a distribution of 5.3, 0.7, 0.4 and 0.6%, respectively (Weaver and Whitsett, 1991, Kishore and Reid, 2001). SP-B (14 kDa) and SP-C (6 kDa) are small, extremely hydrophobic proteins that have important roles in phospholipid packaging, overall organization of the surfactant, adsorption to the air–liquid interface, and in lowering the surface tension at the air–liquid interface in the peripheral air space following expiration. SP-B in particular has been considered to stabilize the phospholipid monolayer via its interaction with DPPC. Similarly, SP-C may be involved in stabilizing the phospholipid layers that form during film compression at low lung volumes.
SP-A and SP-D are large hydrophilic proteins. Their basic structures include an N-terminal triple-helical collagen region and a homotrimeric ligand-recognition domain, called a C-type lectin or carbohydrate recognition domain (CRD). SP-D levels in surfactant lining of the alveolar epithelia are significantly less (∼10-fold) than SP-A. Approximately 75% of SP-D is found generally in the aqueous bronchoalveolar lavage fluid (BALF). SP-A specifically and avidly binds to DPPC (Kuroki and Akino, 1991, Childs et al., 1992, Sano et al., 1998) and is considered to have a major role in surfactant turnover and homeostasis (Table 1). SP-D preferentially binds to phosphatidylinositol (PI) as well as glucosylceramide, both minor components of surfactant that contain sugar moieties (Ogasawara et al., 1992). The CRDs of SP-D bind to the glucosyl moiety of glucosylceramide whereas the interaction with the inositol moiety of PI takes place at the mannose-binding site (Ogasawara et al., 1994, Kishore et al., 1996, Shrive et al., 2003). In addition to their role in surfactant homeostasis, SP-A and SP-D have been shown to be important host defence components against respiratory pathogens and allergens (Holmskov et al., 2003, Kishore et al., 2005, Wright, 2005). The binding of these multimeric SP-A and SP-D proteins to arrays of repetitive carbohydrate moieties commonly found on the surface of viruses, bacteria, yeast and fungi in a Ca2+-dependent, carbohydrate-specific manner can lead to agglutination, enhanced phagocytosis and killing by macrophages and neutrophils (Table 1). SP-A and SP-D can interact with a number of immune cells and modulate their functions (Table 1). phagocytic, chemotactic, oxidative and antigen presenting properties in response to pathogens, allergens, and apoptotic and necrotic cells (Table 1).
Section snippets
Overall structural organization of SP-A and SP-D
SP-A and SP-D belong to a family of mammalian C-type lectins containing collagen regions, called ‘collectins’ (Lu et al., 2002, Holmskov et al., 2003). Their primary structure is organized into four regions: (i) a cysteine-containing N-terminus (required for disulfide-dependent oligomerization) that is linked to (ii) a triple-helical collagen region composed of repeating Gly-X-Y triplets (associated with maintaining the molecules shape, dimension, stability and oligomerization), followed by
Three-dimensional crystallographic structures of trimeric CRDs of SP-A and SP-D
High resolution X-ray crystallographic structural studies of a recombinant fragment of human SP-D (rhSP-D) in the native conformation (Håkansson et al., 1999, Shrive et al., 2003), and in ligand-bound form (Shrive et al., 2003), as well as rat SP-A (rrSP-A; Head et al., 2003) have been reported. The rhSP-D consists of a short stretch of eight N-terminal Gly-Xaa-Yaa collagen-like triplets (residues 179–202), followed by the α-helical coiled-coil neck region (residues 203–235) and the globular
Pathogen recognition and clearance by SP-A and SP-D
SP-A and SP-D are “carbohydrate pattern recognition molecules” and interact with glycoconjugates and lipids on the surface of microorganisms mostly through their CRDs. Pathogen recognition by SP-A and SP-D primarily results from binding of terminal monosaccharide residues present on many pulmonary pathogens. A notable exception is the herpes simplex virus (HSV), which appears to bind to the N-linked oligosaccharides of SP-A molecule (van Iwaarden et al., 1992). The broad selectivity of the
Interaction of SP-A and SP-D with allergens
Malhotra et al. (1993) first showed calcium- and sugar-dependent binding of SP-A to pollen grains from Populus nigra italica (Lombardy Poplar via a 57 kDa and a 7 kDa glycoprotein), Poa pratensis (Kentucky blue grass), Secale cerale (cultivated rye) and Ambrosia elatior (short ragweed) that mediated adhesion of pollen grains to A549 alveolar type II cells. Subsequently, SP-A, SP-D and rhSP-D have been shown to bind house dust mite extract (Dermatophagoides pteronyssinus; Derp) and 3-week culture
Multiple cell surface receptors for SP-A and SP-D
Given the number of immune and surfactant-related functions attributed to SP-A and SP-D, not surprisingly, a number of candidate receptors, both soluble and surface-bound, have been described (Table 2). Receptor molecules for SP-A have been described on the surface of alveolar type II cells, which are not expressed by macrophages, suggesting their exclusive involvement in surfactant homeostasis (Kuroki et al., 1988, Tino and Wright, 1998). There are few candidate receptor molecules whose
Phenotypes of SP-A−/− and SP-D−/− mice
Mice, lacking SP-A mRNA and protein in vivo (SP-A−/−), generated by gene knock-out technology, survive and breed normally, having normal SP-B, SP-C and SP-D levels, phospholipid composition, secretion and clearance, and incorporation of phospholipid precursors. Although there is a complete absence of tubular myelin in SP-A−/− mice, it does not appear to have a significant physiologic effect (Korfhagen et al., 1996).
Mice, bred after disruption of the SP-D gene (SP-D−/−), survive normally in the
Regulation of SP-A and SP-D gene expression
The expression of SP-A and SP-D mRNA is induced during fetal lung development concomitant with an increase in surfactant phospholipid pool. In humans, SP-A mRNA can be detected in bronchiolar cells and precursor alveolar type II cells as early as 20 weeks of gestation (SP-D near 10 weeks) (Khoor et al., 1993) and its level increases dramatically during the third trimester (Pryhuber et al., 1991). This developmental regulation has been linked to thyroid transcription factor-1 (TTF-1) and
Extra-pulmonary aspects of SP-A and SP-D
The alveolar type II cells and non-ciliated bronchial epithelial cells in the lung are major sites of synthesis of both SP-A and SP-D. Compared to SP-A, the synthesis of SP-D, however, is more widespread, and includes epithelial cells in a number of extra-pulmonary sites. Both SP-A and SP-D have been shown to be present in a number of biological fluids and secretions, such as serum (Doyle et al., 1995), amniotic fluid (Miyamura et al., 1994, Cho et al., 1999) and sputum (Masuda et al., 1991),
Conclusions and perspectives
Human SP-A and SP-D appear to play important roles in controlling infection, lung allergy and inflammation. They act against pulmonary pathogens through their ability to aggregate or agglutinate pathogens, recruit and activate neutrophils and macrophages thereby inducing phagocytosis and/or production of superoxide radicals, and have bacteriostatic and fungistatic effect on microbial growth. SP-A and SP-D also offer resistance to allergen challenge by interfering with allergen-IgE interaction,
Acknowledgements
Our research is funded by the European Commission (UK, PW, ALB), the Alexander Humboldt Foundation (UK), the German National Genome Network (NGFN; UK, TC), the Wellcome Trust (TJG, AKS, ALB), CCLRC Daresbury Laboratory (TJG, AKS), Well being of Woman (ALB), the Deutsche Forschungsgemeinschaft through the Graduiertenkolleg GK370 (RG), the Medical Research Council of UK (KBR), and the Council for Scientific and Industrial Research, Delhi, India (TM).
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