SFTPA2

Pulmonary surfactant-associated protein A2 (PSP-A) also known as surfactant protein A2 (SP-A2) is a is_associated_with::protein that in humans is encoded by the SFTPA2 is_associated_with::gene.

Summary
The protein encoded by this gene (SP-A2) is primarily synthesized in lung alveolar type II cells (see is_associated_with::type II pneumocyte), as part of a complex of lipids and proteins known as is_associated_with::pulmonary surfactant. The function of this complex is to reduce is_associated_with::surface tension in the is_associated_with::alveolus and prevent collapse during expiration. The protein component of surfactant helps in the modulation of the innate immune response, and inflammatory processes.



SP-A2 is a member of a subfamily of C-type is_associated_with::lectins called is_associated_with::collectins. Together with SP-A1 (see is_associated_with::SFTPA1), they are the most abundant proteins of is_associated_with::pulmonary surfactant. SP-A2 binds to the is_associated_with::carbohydrates found in the surface of several is_associated_with::microorganisms and helps in the defense against respiratory pathogens.

Surfactant is_associated_with::homeostasis is critical for breathing (and thus survival) in the prematurely born infant, but also for maintaining lung health, and normal lung function throughout life. Quantitative and/or qualitative alterations in surfactant composition and/or function are associated with respiratory diseases.

SFTPA2 expression
The is_associated_with::lung is the main site of SFTPA2 synthesis, but SFTPA2 is_associated_with::mRNA expression has also been detected in the trachea, is_associated_with::prostate, is_associated_with::pancreas, is_associated_with::thymus, colon, is_associated_with::eye, is_associated_with::salivary gland and other tissues. While the majority of these tissues express both SFTPA2 and SFTPA1 transcripts, only SFTPA2 expression was found in the trachea and prostate. Using specific is_associated_with::monoclonal antibodies for is_associated_with::Surfactant protein A, the protein can be detected in lung alveolar is_associated_with::type II pneumocytes, is_associated_with::Clara cells, and is_associated_with::alveolar macrophages, but no extrapulmonary SP-A immunoreactivity was observed.

Gene
SFTPA2 is located in the long arm of is_associated_with::chromosome 10, close to SFTPA1. The SFTPA2 gene is 4556 base pairs in length, and 94% similar to SFTPA1. The structure of SFTPA2 consists of four coding exons (I-IV), and several is_associated_with::5'UTR untranslated exons (A, B, B’, C, C’,D, D’). The expression of SFTPA2 is regulated by cellular factors including proteins, small RNAs (is_associated_with::microRNAs), is_associated_with::glucocorticoids, etc. Its expression is also regulated by is_associated_with::epigenetic and environmental factors.

Differences in the SFTPA2 gene sequence at the is_associated_with::coding region determine SP-A genetic variants or is_associated_with::haplotypes among individuals. More than 30 variants have been identified and characterized for SFTPA2 (and SFTPA1) in the population. SFTPA2 variants result from nucleotide changes in the codons of is_associated_with::amino acids 9, 91, 140, and 223. Three of these do not modify the SP-A2 protein sequence (amino acids 9, 91, and 223), whereas the remaining one results in an is_associated_with::amino acid substitution (amino acid 140). Six SP-A2 variants (1A, 1A0, 1A1, 1A2, 1A3, 1A5) are in higher frequency in the general population. The most frequently found variant is 1A0.

Structure
SP-A2 is a protein of 248 amino acids usually found in large is_associated_with::oligomeric structures. The mature SP-A2 monomer is a 35kDa protein that differs from SP-A1 in four amino acids at the coding region. The structure of SP-A2 monomers consists of four domains: an N-terminal, a collagen-like domain, a neck region, and a carbohydrate recognition domain. The C-terminal carbohydrate recognition domain (CRD) allows binding to various types of is_associated_with::microorganisms and molecules. The amino acid differences that distinguish between SFTPA2 and SFTPA1 genes and between their corresponding variants are located at the collagen-like domain. The amino acid differences that distinguish among SFTPA2 variants are located both at the carbohydrate recognition and the collagen-like domains.

SP-A2 monomers group with other SP-A2 or SP-A1 monomers in trimeric structural subunits of 105kDa. Six of these structures group in 630 kDa structures that resemble flower bouquets. These oligomers contain a total of eighteen SP-A2 and/or SP-A1 monomers.

Functions

 * Binding of is_associated_with::pathogens, is_associated_with::allergens, and other molecules
 * Increasing is_associated_with::phagocytosis and is_associated_with::chemotaxis of is_associated_with::alveolar macrophages
 * Induction of proliferation of immune cells
 * Stimulation of is_associated_with::proinflammatory cytokine production
 * Modulation of the generation of is_associated_with::reactive oxygen species
 * Serving as a is_associated_with::hormone in is_associated_with::parturition
 * Maintaining the structure of is_associated_with::tubular myelin (an is_associated_with::extracellular form of surfactant)

Innate immunity
The role of SFTPA2 in innate immunity has been extensively studied. SP-A has the ability to bind and agglutinate is_associated_with::bacteria, is_associated_with::fungi, is_associated_with::viruses, and other non-biological is_associated_with::antigens. Some of the functions by which both SFTPA2 and is_associated_with::SFTPA1 contribute to is_associated_with::innate immunity include:
 * is_associated_with::opsonization of bacteria for is_associated_with::phagocytosis by is_associated_with::alveolar macrophages
 * recruitment of is_associated_with::monocytes and is_associated_with::neutrophils to the site of is_associated_with::inflammation/is_associated_with::infection
 * enhancement of pathogen-killing mechanisms: is_associated_with::phagocytosis, release of is_associated_with::reactive oxygen species, release of is_associated_with::nitric oxide
 * control of is_associated_with::cytokine production by is_associated_with::immune cells
 * transition of is_associated_with::innate immunity to is_associated_with::adaptive immunity (by interaction with is_associated_with::cell surface receptors of is_associated_with::dendritic cells to allow is_associated_with::antigen presentation)

Environmental insults such as air pollution, and exposure to high concentrations of ozone and particulate matter can affect SP-A expression and function, via mechanisms that involve is_associated_with::epigenetic regulation of SFTPA2 expression.

Clinical significance
Deficiency in SP-A levels is associated with is_associated_with::infant respiratory distress syndrome in prematurely born infants with developmental insufficiency of surfactant production and structural immaturity in the lungs. Alterations of the relative levels of SP-A1 and SP-A2 have been found in is_associated_with::BALF from patients with is_associated_with::cystic fibrosis, is_associated_with::asthma, and is_associated_with::infection.

SFTPA2 genetic variants, is_associated_with::SNPs, haplotypes, and other genetic variations have been associated with acute and chronic is_associated_with::lung disease in several populations of neonates, children, and adults. Mutations in the SFTPA2 gene are found in patients with is_associated_with::interstitial lung disease and is_associated_with::lung cancer. SFTPA2 mutations also associated with pulmonary fibrosis via mechanisms that involve is_associated_with::protein instability and is_associated_with::endoplasmic reticulum stress. Methylation of SFTPA2 and SFTPA1 promoter sequences has also been found in lung cancer tissue.

Gene regulation
Gene expression of SFTPA2 is regulated at different levels including is_associated_with::gene transcription, post-transcriptional processing, stability and is_associated_with::translation (biology) of mature mRNA. One of the important features of human surfactant protein A mRNAs is that they have a variable is_associated_with::five prime untranslated region (5’UTR) generated from splicing variation of exons A, B, C, and D. At least 10 forms of human SFTPA2 and is_associated_with::SFTPA1 5’UTRs have been identified that differ in is_associated_with::nucleotide sequence, length, and relative amount. Most SFTPA2 specific 5’UTRs include exon B. This 30-nucleotide long sequence has been shown to enhance both is_associated_with::gene transcription and protein is_associated_with::translation (biology), and plays a key role in the differential regulation of SFTPA2 and SFTPA1 expression. Both ABD and ABD’ are the most represented forms among SFTPA2 transcripts (~49% each), and experimental work has shown that this sequence can stabilize mRNA, enhance translation, and activate cap-independent is_associated_with::eukaryotic translation. Exon B of SFTPA2 also binds specific proteins (e.g. is_associated_with::14-3-3) that may enhance translation, in a sequence- and secondary structure- specific way. While differences at the 5’UTR are shown to regulate both transcription and translation, polymorphisms at the 3’UTR of SP-A2 variants are shown to primarily, differentially affect translation efficiency via mechanisms that involve binding of proteins and/or [microRNAs]. The impact of this regulation on SFTPA2 relative protein levels may contribute to individual differences in susceptibility to lung disease. Environmental insults and pollutants also affect SFTPA2 expression. Exposure of lung cells to is_associated_with::particulate matter affects splicing of 5’UTR exons of SFTPA2 transcripts. Pollutants and viral infections also affect SFTPA2 translation mechanisms (see is_associated_with::eukaryotic translation, is_associated_with::translation (biology)).