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Review
. 2016 May 25;583(1):48-57.
doi: 10.1016/j.gene.2016.02.044. Epub 2016 Mar 3.

Serum amyloid A1: Structure, function and gene polymorphism

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Review

Serum amyloid A1: Structure, function and gene polymorphism

Lei Sun et al. Gene. .

Abstract

Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1-SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.

Keywords: Acute-phase response; Gene polymorphism; Induced expression; Inflammation; Lipid metabolism; Serum amyloid A.

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Conflict of interest statement

Conflict of interest statement

The authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1. Schematic depiction of SAA1 and its protein sequence variations
A, linear representation of human SAA1 showing its N-terminal signal peptide of 18 amino acids and the mature SAA1 protein. The 4 α-helices and the C-terminal tail reported recently based on a SAA1.1 crystal structure (Lu et al., 2014) are marked with different colors and their relative positions are indicated. B, comparison of the amino acid sequence encoded by the human SAA1 allelic variants. Mature protein sequences of the 5 human SAA1 variants are shown (based on Sipe et al., 1999). Different amino acids in each of the variants are highlighted in red. Amino acids corresponding to the α-helices and the C-terminal tail are underlined.
Figure 2
Figure 2. Organization of the human SAA gene cluster and single nucleotide polymorphisms in the human SAA1 gene
A, linear map of human SAA1 relative to other human SAA genes including the pseudogene SAA3P, on chromosome 11p15.1 (Betts et al., 1991; Sellar et al., 1994). Arrows depict the orientation of the genes. The organization of exons in SAA1 is based on GenBank entries (from top) NM_199161, NM_001178006, and NM_000331, respectively. The human SAA1 gene has the typical 4-exon and 3-intron organization seen in other species. The coding regions in the exons are marked in black and non-coding regions are marked in gray. B, the confirmed human SAA1 SNPs (Leow et al., 2013) are marked in the SAA1 gene. The numbers in each name indicate nucleotide positions of the SNPs, and substitutions in nucleotides are shown in the first set of parentheses. The second set of parentheses contain the names of the SNPs.
Figure 3
Figure 3. Comparison of the amino acid sequence of human SAA1.1 with SAA isoforms from mice and pigs
Mature protein sequences of the known SAA isoforms are shown, with identical amino acids marked with asterisks (*) and unmatched gaps marked with dashes (−). The sequences shown are derived from NCBI (http://www.ncbi.nlm.nih.gov) and include human SAA1.1 (NP_000322.2), mouse Saa1.1 (NP_035444.1), mouse Saa2.1 (NP_033143.1), mouse Saa2.2 (AAA19818.1), and porcine SAA2 (NP_001038017.1). Porcine SAA-like (not shown) is available at XP_003122986.2 of NCBI. These SAA proteins are listed according to the nomenclature of J. Sipe (1999). Note that the pre-1999 nomenclature is still in use by NCBI, such that the mouse Saa1.1 shown in this figure is marked as Saa2, and the mouse Saa2.1 shown is labeled as Saa1, in the NCBI protein database.

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