Surfactant protein A2

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

SFTPA2
Identifiers
Aliases	SFTPA2, COLEC5, PSAP, PSP-A, PSPA, SFTP1, SFTPA2B, SP-A, SPA2, SPAII, surfactant protein A2, SP-2A, ILD2
External IDs	OMIM: 178642; MGI: 109518; HomoloGene: 121995; GeneCards: SFTPA2; OMA:SFTPA2 - orthologs
Gene location (Human) Chr. Chromosome 10 (human) Band 10q22.3 Start 79,555,852 bp End 79,560,407 bp
Gene location (Mouse) Chr. Chromosome 14 (mouse) Band 14 B|14 22.36 cM Start 40,853,739 bp End 40,858,409 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lower lobe of lung visceral pleura upper lobe of lung right lung upper lobe of left lung apex of heart bronchial epithelial cell cerebellar hemisphere right hemisphere of cerebellum trachea Top expressed in right lung lobe left lung left lung lobe trachea alveolar duct sexually immature organism pulmonary alveolus carotid body aorta liver More reference expression data BioGPS n/a
Gene ontology Molecular function carbohydrate binding lipopolysaccharide binding monosaccharide binding Cellular component extracellular region clathrin-coated endocytic vesicle collagen lamellar granule endoplasmic reticulum membrane extracellular space multivesicular body rough endoplasmic reticulum Biological process respiratory gaseous exchange by respiratory system toll-like receptor signaling pathway surfactant homeostasis positive regulation of phagocytosis developmental process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 729238 20387 Ensembl ENSG00000185303 ENSMUSG00000021789 UniProt Q8IWL1 P35242 Q9CQI1 RefSeq (mRNA) NM_001098668 NM_001320813 NM_001320814 NM_023134 RefSeq (protein) NP_001092138 NP_001307742 NP_001307743 NP_075623 Location (UCSC) Chr 10: 79.56 – 79.56 Mb Chr 14: 40.85 – 40.86 Mb PubMed search
Wikidata
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Summary

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

Alveolar sac region of the lung - TEM

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

Surfactant 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 lung is the main site of SFTPA2 synthesis, but SFTPA2 mRNA expression has also been detected in the trachea, prostate, pancreas, thymus, colon, eye, 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 monoclonal antibodies for Surfactant protein A, the protein can be detected in lung alveolar type II pneumocytes, Club cells, and alveolar macrophages, but no extrapulmonary SP-A immunoreactivity was observed.

Gene

SFTPA2 is located in the long arm of 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 5'UTR untranslated exons (A, B, B’, C, C’, D, D’). The expression of SFTPA2 is regulated by cellular factors including proteins, small RNAs (microRNAs), glucocorticoids, etc. Its expression is also regulated by epigenetic and environmental factors.

Differences in the SFTPA2 gene sequence at the coding region determine SP-A genetic variants or 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 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 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 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 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 pathogens, allergens, and other molecules
• Increasing phagocytosis and chemotaxis of alveolar macrophages
• Induction of proliferation of immune cells
• Stimulation of proinflammatory cytokine production
• Modulation of the generation of reactive oxygen species
• Serving as a hormone in parturition
• Maintaining the structure of tubular myelin (an 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 bacteria, fungi, viruses, and other non-biological antigens. Some of the functions by which both SFTPA2 and SFTPA1 contribute to innate immunity include:

• opsonization of bacteria for phagocytosis by alveolar macrophages
• recruitment of monocytes and neutrophils to the site of inflammation/infection
• enhancement of pathogen-killing mechanisms: phagocytosis, release of reactive oxygen species, release of nitric oxide
• control of cytokine production by immune cells
• transition of innate immunity to adaptive immunity (by interaction with cell surface receptors of dendritic cells to allow 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 epigenetic regulation of SFTPA2 expression.

Clinical significance

Deficiency in SP-A levels 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 BALF from patients with cystic fibrosis, asthma, and infection.

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

SFTPA2 mRNA transcript variants

Variant id	5’UTR splice	Coding	3’UTR sequence	GenBank id
ABD1A	ABD	1A	1A	HQ021432
ABD1A0	ABD	1A0	1A0	HQ021421
ABD1A1	ABD	1A1	1A1	HQ021422
ABD1A2	ABD	1A2	1A2	HQ021423
ABD1A3	ABD	1A3	1A3	HQ021424
ABD1A5	ABD	1A5	1A5	HQ021425
ABD'1A	ABD'	1A	1A	HQ021426
ABD'1A0	ABD'	1A0	1A0	HQ021427
ABD'1A1	ABD'	1A1	1A1	HQ021428
ABD'1A2	ABD'	1A2	1A2	HQ021429
ABD'1A3	ABD'	1A3	1A3	HQ021430
ABD'1A5	ABD'	1A5	1A5	HQ021431
SFTPA2	ABD’	1A2	1A0	NM_001098668.2

Gene regulation

Gene expression of SFTPA2 is regulated at different levels including gene transcription, post-transcriptional processing, stability and translation (biology) of mature mRNA. One of the important features of human surfactant protein A mRNAs is that they have a variable 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 SFTPA1 5’UTRs have been identified that differ in 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 gene transcription and protein 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 eukaryotic translation. Exon B of SFTPA2 also binds specific proteins (e.g. 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 particulate matter affects splicing of 5’UTR exons of SFTPA2 transcripts. Pollutants and viral infections also affect SFTPA2 translation mechanisms (see eukaryotic translation, translation (biology)).

See also

• Pulmonary surfactant
• Surfactant protein A
• Collectin

Further reading

• Floros J, Hoover RR (November 1998). "Genetics of the hydrophilic surfactant proteins A and D". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1408 (2–3): 312–22. doi:10.1016/S0925-4439(98)00077-5. PMID 9813381.
• Katyal SL, Singh G, Locker J (April 1992). "Characterization of a second human pulmonary surfactant-associated protein SP-A gene". American Journal of Respiratory Cell and Molecular Biology. 6 (4): 446–52. doi:10.1165/ajrcmb/6.4.446. PMID 1372511.
• Voss T, Melchers K, Scheirle G, Schäfer KP (January 1991). "Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: implications for the chain composition of natural human SP-A". American Journal of Respiratory Cell and Molecular Biology. 4 (1): 88–94. doi:10.1165/ajrcmb/4.1.88. PMID 1986781.
• Haagsman HP, White RT, Schilling J, Lau K, Benson BJ, Golden J, Hawgood S, Clements JA (December 1989). "Studies of the structure of lung surfactant protein SP-A". The American Journal of Physiology. 257 (6 Pt 1): L421–9. doi:10.1152/ajplung.1989.257.6.L421. PMID 2610270.
• White RT, Damm D, Miller J, Spratt K, Schilling J, Hawgood S, Benson B, Cordell B (1985). "Isolation and characterization of the human pulmonary surfactant apoprotein gene". Nature. 317 (6035): 361–3. Bibcode:1985Natur.317..361W. doi:10.1038/317361a0. PMID 2995821. S2CID 4357498.
• Floros J, Steinbrink R, Jacobs K, Phelps D, Kriz R, Recny M, Sultzman L, Jones S, Taeusch HW, Frank HA (July 1986). "Isolation and characterization of cDNA clones for the 35-kDa pulmonary surfactant-associated protein". The Journal of Biological Chemistry. 261 (19): 9029–33. doi:10.1016/S0021-9258(19)84483-6. PMID 3755136.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• McCormick SM, Boggaram V, Mendelson CR (April 1994). "Characterization of mRNA transcripts and organization of human SP-A1 and SP-A2 genes". The American Journal of Physiology. 266 (4 Pt 1): L354–66. doi:10.1152/ajplung.1994.266.4.L354. PMID 8179012.
• Kölble K, Lu J, Mole SE, Kaluz S, Reid KB (August 1993). "Assignment of the human pulmonary surfactant protein D gene (SFTP4) to 10q22-q23 close to the surfactant protein A gene cluster". Genomics. 17 (2): 294–8. doi:10.1006/geno.1993.1324. PMID 8406480.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Stuart GR, Lynch NJ, Day AJ, Schwaeble WJ, Sim RB (December 1997). "The C1q and collectin binding site within C1q receptor (cell surface calreticulin)". Immunopharmacology. 38 (1–2): 73–80. doi:10.1016/S0162-3109(97)00076-3. PMID 9476117.
• Karinch AM, Deiter G, Ballard PL, Floros J (June 1998). "Regulation of expression of human SP-A1 and SP-A2 genes in fetal lung explant culture". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1398 (2): 192–202. doi:10.1016/S0167-4781(98)00047-5. PMID 9689918.
• Saitoh H, Okayama H, Shimura S, Fushimi T, Masuda T, Shirato K (August 1998). "Surfactant protein A2 gene expression by human airway submucosal gland cells". American Journal of Respiratory Cell and Molecular Biology. 19 (2): 202–9. doi:10.1165/ajrcmb.19.2.3239. PMID 9698591.
• Goss KL, Kumar AR, Snyder JM (October 1998). "SP-A2 gene expression in human fetal lung airways". American Journal of Respiratory Cell and Molecular Biology. 19 (4): 613–21. CiteSeerX 10.1.1.322.5594. doi:10.1165/ajrcmb.19.4.3155. PMID 9761758.
• Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Silva W, Zago MA, Bordin S, Costa FF, Goldman GH, Carvalho AF, Matsukuma A, Baia GS, Simpson DH, Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ (March 2000). "Shotgun sequencing of the human transcriptome with ORF expressed sequence tags". Proceedings of the National Academy of Sciences of the United States of America. 97 (7): 3491–6. Bibcode:2000PNAS...97.3491D. doi:10.1073/pnas.97.7.3491. PMC 16267. PMID 10737800.
• Wang G, Phelps DS, Umstead TM, Floros J (May 2000). "Human SP-A protein variants derived from one or both genes stimulate TNF-alpha production in the THP-1 cell line". American Journal of Physiology. Lung Cellular and Molecular Physiology. 278 (5): L946–54. doi:10.1152/ajplung.2000.278.5.l946. PMID 10781424.
• Berg T, Leth-Larsen R, Holmskov U, Højrup P (November 2000). "Structural characterisation of human proteinosis surfactant protein A". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1543 (1): 159–73. doi:10.1016/S0167-4838(00)00184-9. PMID 11087951.
• Lin Z, deMello D, Phelps DS, Koltun WA, Page M, Floros J (2002). "Both human SP-A1 and Sp-A2 genes are expressed in small and large intestine". Pediatric Pathology & Molecular Medicine. 20 (5): 367–86. doi:10.3109/15513810109168621. PMID 11552738.
• Madan T, Saxena S, Murthy KJ, Muralidhar K, Sarma PU (October 2002). "Association of polymorphisms in the collagen region of human SP-A1 and SP-A2 genes with pulmonary tuberculosis in Indian population". Clinical Chemistry and Laboratory Medicine. 40 (10): 1002–8. doi:10.1515/CCLM.2002.174. PMID 12476938. S2CID 20022095.