Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense.
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-terminal peptide 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 recombinant acute phase isoform variant of human SAA 1.1 (SAAp) readily forms ion-channels in planar lipid 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 in dicates 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.
Hirakura
Yutaka
Y
Department of Psychiatry, Neuropsychiatric Institute, UCLA School of Medicine, 90024, USA.
Carreras
Isabel
I
Sipe
Jean D
JD
Kagan
Bruce L
BL
D000595:Amino Acid Sequence; D001053:Apolipoproteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D007473:Ion Channels / Q000096:biosynthesis*; D008051:Lipid Bilayers; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D001053:Apolipoproteins; D007473:Ion Channels; D008051:Lipid Bilayers; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein