Serum amyloid A - a review

Abstract

Serum amyloid A (SAA) proteins were isolated and named over 50 years ago. They are small (104 amino acids) and have a striking relationship to the acute phase response with serum levels rising as much as 1000-fold in 24 hours. SAA proteins are encoded in a family of closely-related genes and have been remarkably conserved throughout vertebrate evolution. Amino-terminal fragments of SAA can form highly organized, insoluble fibrils that accumulate in "secondary" amyloid disease. Despite their evolutionary preservation and dynamic synthesis pattern SAA proteins have lacked well-defined physiologic roles. However, considering an array of many, often unrelated, reports now permits a more coordinated perspective. Protein studies have elucidated basic SAA structure and fibril formation. Appreciating SAA's lipophilicity helps relate it to lipid transport and metabolism as well as atherosclerosis. SAA's function as a cytokine-like protein has become recognized in cell-cell communication as well as feedback in inflammatory, immunologic, neoplastic and protective pathways. SAA likely has a critical role in control and possibly propagation of the primordial acute phase response. Appreciating the many cellular and molecular interactions for SAA suggests possibilities for improved understanding of pathophysiology as well as treatment and disease prevention.

Keywords: SAA; Serum amyloid A; acute phase response (APR); amyloidosis; apolipoprotein; arthritis; atherosclerosis; cytokine; inflammation; lipopolysaccharide (LPS); liver; myeloid-derived suppressor cells (MDSC).

Fig. 1

a Consensus amino acid sequence for human SAA (SAA1 shown although variants are recognized as well – see Fig. 2) b Comparison of SAA sequences in different organisms. Conserved residues noted in boxes. (USCS Genome Browser [GRCh38/hg38] Assembly)

Fig. 2

Reported amino acid variants for SAA1 and SAA2 in humans. Underlined regions appear invariant.

Fig. 3

a Monomeric three-dimensional structure of SAA1.1 (Lu et al. (2014), Copyright [2014], National Academy of Sciences, used by permission). Note 4 α-helices 1 (aa 1-27), 2 (aa 32-47), 3 (aa 50-69), 4 (aa 73-88) and C-terminal tail (aa 89-104). b Proposed model for SAA interaction on HDL surface showing potential binding sites to receptors and other molecules. (Frame and Gursky (2016), Copyright John Wiley and Sons, 2016, used by permission)

Fig. 4

Proposed scheme for SAA fibril formation. a HDL-bound SAA dissociates from HDL. b {S}AA enters cell via clathrin-coated pits to reside in low pH lysosomal environment. c {S}AA monomers undergo structural rearrangement(s) within lysosome. d AA oligomers form within cells. e Lysis of lysosomal and cellular membranes leads to extracellular oligomers and debris from necrotic cells. f AA oligomers extend into fibrils based on β-pleated sheet domain interactions and become visible as tissue “amyloid” deposits with congo red binding. (modified after Claus et al. (2017), Copyright John Wiley and Sons, 2017, used by permission). As described in the text, cleavage of SAA occurs during this process, generally yielding a 76 aa N-terminal fragment. Cleavage may involve a serine protease on the cell surface (Lavie et al. 1978) but the precise site at which this occurs remains unestablished and the undefined nature of the intracellular species in the early stages (a-c) is indicated by {S}AA. By stage (d) the AA (post-cleavage) species likely predominates

Fig. 5

a Organization of the four members of the human Saa gene family on chromosome 11p. b Exon/intron structure of human SAA1 gene (a common pattern for all Saa gene family members)

Fig. 6

Promoter maps for mammalian SAA genes showing regions for transcription-factor binding. Transcription begins at the arrow (+1). Sites are identified for NF-κB, C/EBP, AP-2, SAS (binds SAF and SEF-1) and YY1. SEF is a factor identified in the mouse distal response element. (Uhlar and Whitehead (1999a), Copyright John Wiley and Sons, 2011, used by permission)

Fig. 7

Proposed relationships between cytokines, chemokines and participating cells in APR consistent with current data. Note 3 distinct cell types: 1) macrophages, 2) hepatocytes, 3) myeloid-derived suppressor cells [MDSC]. MDSC can be mobilized from bone marrow and undergo further differentiation in spleen and elsewhere

Fig. 8

Proposed sites for participation of SAA in atherosclerosis. (King et al. (2011), Copyright Lippincott Williams & Wilkins, 2011, used by permission.)