Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

Abstract

Purpose of Review This review addresses normal and pathologic functions of serum amyloid A (SAA), an enigmatic biomarker of inflammation and protein precursor of AA amyloidosis, a life-threatening complication of chronic inflammation. SAA is a small, highly evolutionarily conserved acute-phase protein whose plasma levels increase up to one thousand-fold in inflammation, infection, or after trauma. The advantage of this dramatic but transient increase is unclear, and the complex role of SAA in immune response is intensely investigated. This review summarizes recent advances in our understanding of the structure-function relationship of this intrinsically disordered protein, outlines its newly emerging beneficial roles in lipid transport and inflammation control, and discusses factors that critically influence its misfolding in AA amyloidosis. Recent Findings High-resolution structures of lipid-free SAA in crystals and fibrils have been determined by x-ray crystallography and electron cryo-microscopy. Low-resolution structural studies of SAA-lipid complexes, together with biochemical, cell-based, animal model, genetic, and clinical studies, have provided surprising new insights into a wide range of SAA functions. An emerging vital role of SAA is lipid encapsulation to remove cell membrane debris from sites of injury. The structural basis for this role has been proposed. The lysosomal origin of AA amyloidosis has solidified, and its molecular and cellular mechanisms have emerged. Summary Recent studies have revealed molecular underpinnings for understanding complex functions of this Cambrian protein in lipid transport, immune response, and amyloid formation. These findings help guide the search for much-needed targeted therapies to block the protein deposition in AA amyloidosis.

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“…Frontiers in Marine Science | www.frontiersin.org acute inflammatory response, with a significant enhancement of serum CRP and SAA levels following organism inflammation, injury, or infection (Pepys et al, 1978;Lindhorst et al, 1997;Pepys and Hirschfield, 2003;MacCarthy et al, 2008;Rosani et al, 2016;Franco-Martinez et al, 2019;Bello-Perez et al, 2020;Gursky, 2020;Williams et al, 2020). Derebe et al (2014) reported that vitamin A deficiency may lead to an immune deficiency in mice with decreasing the abundances of SAAs in small intestine and liver.…”

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