Surfactant protein A amino acids Glu195 and Arg197 are essential for receptor binding, phospholipid aggregation, regulation of secretion, and the facilitated uptake of phospholipid by type II cells.

McCormack, F X; Kuroki, Yoshio; Stewart, Jennifer; Mason, Robert J.; Voelker, Dennis R.

doi:10.1016/s0021-9258(18)43952-x

Cited by 81 publications

(39 citation statements)

References 30 publications

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“…SP-A mRNA in adult lung tissue has been localized in the epithelial type II cells by in situ hybridization (39), as has the SP-A protein by immunohistochemistry and immunoelectron microscopy (40). Although there have been published works using SP-A from various species (41)(42)(43)(44)(45)(46)(47)(48) the focus and the reference points discussed in this review are primarily those of human SP-A1 and SP-A2. Thus, here we focus on functional and structural differences between human SP-A1 and SP-A2 and/or among their corresponding variants, as well as on their differential ability to regulate processes in alveolar cells and impact survival of the organism.…”

Section: Introductionmentioning

confidence: 99%

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

et al. 2021

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The human innate host defense molecules, SP-A1 and SP-A2 variants, differentially affect survival after infection in mice and in lung transplant patients. SP-A interacts with the sentinel innate immune cell in the alveolus, the alveolar macrophage (AM), and modulates its function and regulation. SP-A also plays a role in pulmonary surfactant-related aspects, including surfactant structure and reorganization. For most (if not all) pulmonary diseases there is a dysregulation of host defense and inflammatory processes and/or surfactant dysfunction or deficiency. Because SP-A plays a role in both of these general processes where one or both may become aberrant in pulmonary disease, SP-A stands to be an important molecule in health and disease. In humans (unlike in rodents) SP-A is encoded by two genes (SFTPA1 and SFTPA2) and each has been identified with extensive genetic and epigenetic complexity. In this review, we focus on functional, structural, and regulatory differences between the two SP-A gene-specific products, SP-A1 and SP-A2, and among their corresponding variants. We discuss the differential impact of these variants on the surfactant structure, the alveolar microenvironment, the regulation of epithelial type II miRNome, the regulation and function of the AM, the overall survival of the organism after infection, and others. Although there have been a number of reviews on SP-A, this is the first review that provides such a comprehensive account of the differences between human SP-A1 and SP-A2.

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Section: Introductionmentioning

confidence: 99%

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

et al. 2021

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“…In these studies, the R197D and R197N mutants were shown to alter the ability of SP-A to aggregate DPPC liposomes. In other studies, an SP-A double mutation (E195Q/R197D) that changed the mannose specificity to galactose produced a mutant that would bind but not aggregate DPPC liposomes . In addition, alanine substitutions of several lectin site residues showed a loss of DPPC liposome binding and aggregation .…”

Section: Discussionmentioning

confidence: 92%

“…They also showed weakened ability to aggregate liposomes despite avid lipid binding, a profile that had been reported for the E195Q/R197D SP-A variant, perhaps related to effects of mutations on the orientation of the CRDs on the liposomal surface that affect lateral protein−protein interactions between CRDs. 41 All of the proteins that bound DPPC, i.e., WT SP-A and the DED and R197N mutants, were capable of binding lipid A in a calcium-independent manner. It should be noted that although not required for binding, calcium has been reported to promote the formation of SP-A/LPS aggregates, and in the presence of SP-A to influence the distribution and behavior of lipids in mixed DPPC/LPS membranes.…”

Section: ■ Discussionmentioning

confidence: 95%

“…In other studies, an SP-A double mutation (E195Q/R197D) that changed the mannose specificity to galactose produced a mutant that would bind but not aggregate DPPC liposomes. 41 In addition, alanine substitutions of several lectin site residues showed a loss of DPPC liposome binding and aggregation. 49 Overall, these data implied a critical role for the CRD lectin site in the determination of lipid binding preferences of SP-A.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Liposome Aggregation. Liposome aggregation experiments were performed as previously described, 41 with the following modifications. Unilamellar vesicles were produced by probe sonication of DPPC/PC/cholesterol/18:0−18:2 PC lipid mixtures (1:1:0.15:0.15) in 10 mM HEPES (pH 7.5) and 150 mM NaCl buffer at 25 °C.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

See 2 more Smart Citations

Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop

Rynkiewicz

Cafarella

et al. 2017

Biochemistry

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Lung surfactant proteins (SPs) play critical roles in surfactant function and innate immunity. SP-A and SP-D, members of the collectin family of C-type lectins, exhibit distinct ligand specificities, effects on surfactant structure, and host defense functions despite extensive structural homology. SP-A binds to dipalmitoylphosphatidylcholine (DPPC), the major surfactant lipid component, but not phosphatidylinositol (PI), whereas SP-D shows the opposite preference. Additionally, SP-A and SP-D recognize widely divergent pathogen-associated molecular patterns. Previous studies suggested that a ligand-induced surface loop conformational change unique to SP-A contributes to lipid binding affinity. To test this hypothesis and define the structural features of SP-A and SP-D that determine their ligand binding specificities, a structure-guided approach was used to introduce key features of SP-D into SP-A. A quadruple mutant (E171D/P175E/R197N/K203D) that introduced an SP-D-like loop-stabilizing calcium binding site into the carbohydrate recognition domain was found to interconvert SP-A ligand binding preferences to an SP-D phenotype, exchanging DPPC for PI specificity, and resulting in the loss of lipid A binding and the acquisition of more avid mannan binding properties. Mutants with constituent single or triple mutations showed alterations in their lipid and sugar binding properties that were intermediate between those of SP-A and SP-D. Structures of mutant complexes with inositol or methyl-mannose revealed an attenuation of the ligand-induced conformational change relative to wild-type SP-A. These studies suggest that flexibility in a key surface loop supports the distinctive lipid binding functions of SP-A, thus contributing to its multiple functions in surfactant structure and regulation, and host defense.

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Collectins: sentinels of innate immunity

Gupta

Surolia

2007

BioEssays

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Collectins, present in plasma and on mucosal surfaces, are humoral molecules of the innate immune system. They were discovered a hundred years ago in 1906 as the first association of an animal lectin with the immune system. They are a family of calcium-dependent lectins that recognize pathogen-associated molecular patterns. They share a similar modular domain architecture consisting of four regions; a cysteine-rich N-terminal domain, a collagen-like region, an alpha-helical neck domain and a C-terminal carbohydrate recognition domain. There have been eight collectins members defined so far, of which, MBL, SP-A and SP-D are the most characterized. Collectins represent the first line of host defense. Upon recognition of the infectious agents, collectins put into action effector mechanisms like direct opsonization, neutralization, agglutination, complement activation and phagocytosis to curb the microbial growth. In addition, they also modulate inflammatory and allergic responses and apoptotic cell clearance. These functions limit infection and subsequently modulate the adaptive immune responses. The role of collectins, their structure, function, characteristics and clinical significance are reviewed in this article.

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Surfactant protein A amino acids Glu195 and Arg197 are essential for receptor binding, phospholipid aggregation, regulation of secretion, and the facilitated uptake of phospholipid by type II cells.

Cited by 81 publications

References 30 publications

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop

Collectins: sentinels of innate immunity

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