Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense

• Published in: Amyloid Vol. 9; no. 1; pp. 13 - 23
• Main Authors: Hirakura, Yutaka, Carreras, Isabel, Sipe, Jean D., Kagan, Bruce L.
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 2002; Taylor & Francis
• Subjects: acute phase reactants; Amino Acid Sequence; Apolipoproteins - chemistry; Apolipoproteins - genetics; Apolipoproteins - physiology; cytotoxicity; Escherichia coli - genetics; Humans; inflammation; Ion Channels - biosynthesis; Lipid Bilayers; membranes; Molecular Sequence Data; pores; Protein Structure, Secondary; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Sequence Homology, Amino Acid; Serum Amyloid A Protein - chemistry; Serum Amyloid A Protein - genetics; Serum Amyloid A Protein - physiology
• ISSN: 1350-6129; 1744-2818
• DOI: 10.3109/13506120209072440

Serum amyloid A (SAA) is a family of closely related apolipoproteins associated with high density lipoprotein (HDL). Subclasses of SAA isoforms are differentially expressed constitutively and during inflammation. During states of infection or inflammation, levels of HDL, bound, acute phase isoforms of SAA rise as much as 1000-fold in the serum, suggesting that it might play a role in host defense. Following recurrent or chronic inflammation, an N-terminalpeptide fragment of SAA known as amyloid A (AA) assembles into fibrils causing extensive damage to spleen, liver, and kidney, and rapidly progressing to death. In the present paper, we report the novel finding that a recombi-nant acute phase isoform variant of human SAA1.1 (SAAp) readily forms ion-channels in planar liptd bilayer membranes at physiologic concentrations. These channels are voltage-independent, poorly selective, and are relatively long-lived. This type of channel would place a severe metabolic strain on various kinds of cells. Expression of human SAA 1.1 in bacteria induces lysis of bacterial cells, while expression of the constitutive isoform (human SAA4) does not. Secondary structural analysis of the SAA isoforms indicates a strong hydrophobicity of the N-terminal of the acute phase isoform relative to the constitutive SAA4 isoform, which may be responsible for the bactericidal activity of the former, in keeping with the notion that SAA 1 targets cell membranes and forms channels in them. Channel formation may thus be related to a host defense role of acute phase SAA isoforms and may also be the mechanism of end organ damage in AA and other amyloidoses.