Human Lung Surfactant Protein D (h-SPD)

Jacob Smith '23 and Polina Sonin '23

Contents:

I. Introduction

Human lung surfactant protein D (hSP-D) is a calcium-dependent protein, involved in the lung innate immune response. One of the protein's main roles is regulation of the pulmonary surfactant lipid levels. This is accomplished by hSP-D through recognizing carbohydrate ligands on the surface of the pathogens. The unique asymmetrical structure of this protein is due to one of its three tyrosine side chains being attached to the center coil. This causes a cleft that is largely positively charged. The positive charge allows the protein to bind to negatively charged structures like lipopolysaccharides. This process regulates a part of the inflammatory system of the lungs.

Not only does hSP-D have an interesting structure and function, but it has recently attracted a lot of attention because of COVID-19. Recent studies have been done on how the virus affects the level of observed hSP-D function. Elevated levels of hSP-D were found to indicate a rise in alveolar damage. Due to its anti-inflammatory function hSP-D is prevalent in multiple pulmonary diseases.  

II. General Structure

In the body hSP-D is found as an x shaped structure with four trimers. It forms a trimeric coiled coil of three polypeptide chains labeled A, B, and C. The neck region of the protein makes 8 helical turns before it is terminated by the helix breaker Pro 235 . The neck region is made up of hydrophobic clusters . These are essential to help the carbohydrate recognition domains (CRDs)interact with the neck region of the protein. There are three Lys246 residues that form long salt bridges with Glu232 to relieve unfavorable charge interactions of residues of the same charge. . All of this is driven by 3 calcium ions bound at each monomer .

hSP-D has general symmetry except for a Tyr side chain present in all three domains . In chain A and B Tyr 228 is more exposed and can hydrogen bond to water. In chain C Tyr 228 C is buried in the interior of the coiled coil. Due to steric reasons chains A and B cannot adopt the same conformation as chain C. Tyr 228 A and Tyr 228 B are able to swing the Tyr228 out to hydrogen bond with water while the Tyr228 on C remains tucked inside the center of the coil. The buried residue makes up the center of a van der Walls interaction between all three tyrosines. This is seen to be important in the oligomerization of the protein to be exclusively trimeric.

 

III. h-SPD and Covid

h-SPD is responsible for regulating the pulmonary inflammatory response. As a part of the front line immune defence proteins, h-SPD binds glycosylated structures on the attacking pathogens, such as viruses promoting a rapid clearance from the lungs. It was found that the serum levels of h-SPD in covid patients with moderate to severe symptoms are higher than those in the asymptomatic patients and patients with mild symptoms. h-SPD is released by the type II alveolar cells. Due to the amino acid breakdown and chemical modifications in the lung pulmonary h-SPD is converted into a trimeric form. Air-blood barrier in the lungs breaks allowing the pulmonary h-SPD to enter the circulation, therefore h-SPD is an indicator of lung damage. h-SDP was therefore found to be useful in predicting the severity of the virus outcome in covid-19 patients.


Fig. 1. The dot plots shows the correlation between h-SPD and the clinical severity of disease (Alay et al. 2021).

IV. Implications

Among the biological implications of h-SPD are pulmonary host defence by mediating pathogen extinguishing, regulating allergic responses, and fighting lung inflammation. Multiple studies have shown that patients with chronic pulmonary disease have elevated levels of serum h-SPD compared to healthy controls. Which adds flexibility and alters the conserved structural calcium sites located between the long and short loops of the CRD , thereby increasing its ability to interact with non-terminal saccharides. h-SPD is also seen to have mutations on Asn324 and Asn330 Along with several non-lectin site residues on the surface of the CRD of h-SPD form a bulge that help neutralize influenza A virus (IAV). Therefore h-SPD is considered a disease marker for multiple diseases, such as pulmonary fibrosis, lung involvement in systemic sclerosis, and IAV.

VI. References

Alay, H., & Laloglu, E. (2021). The role of angiopoietin 2 and surfactant protein D levels in SARSCoV2 related lung injury: A prospective, observational, cohort study. Journal of Medical Virology, 93(10), 6008-6015.

Arroyo, R., Grant, S. N., Colombo, M., Salvioni, L., Corsi, F., Truffi, M., ... & Kingma, P. S. (2021). Full-Length Recombinant hSP-D Binds and Inhibits SARS-CoV-2. Biomolecules, 11(8), 1114.

Hakansson, K., Lim, N. K., Hoppe, H. J., & Reid, K. B. (1999). Crystal structure of the trimeric ?-helical coiled-coil and the three lectin domains of human lung surfactant protein D. Structure, 7(3), 255-264.

Pilecki, B., Wulf-Johansson, H., Stottrup, C., Jorgensen, P. T., Djiadeu, P., Nexoe, A. B., ... & Sorensen, G. L. (2018). Surfactant protein D deficiency aggravates cigarette smoke-induced lung inflammation by upregulation of ceramide synthesis. Frontiers in immunology, 9, 3013.Chicago

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