Serum Amyloid A (SAA) & Amyloid A Amyloidosis
Serum amyloid A (SAA) proteins are a family of apolipoproteins
found predominantly associated with high-density lipoprotein (HDL)
in plasma, with different isoforms being unequally expressed constitutively
and in response to inflammatory stimuli. Although synthesized primarily
in the liver, extrahepatic tissue/cellular expression of SAA has
been widely documented. SAA has been linked to functions related
to inflammation, pathogen defense, HDL metabolism, and cholesterol
transport and thereby has been implicated in several pathological
conditions including atherosclerosis, rheumatoid arthritis, Alzheimer’s
disease, and cancer. SAA is known best for its role during the acute
phase response to an inflammatory stimulus such as infection, tissue
injury, and trauma. During active inflammation the concentration of SAA
in plasma can increase up to 1,000-fold within 24 hours. It is believed
that persistently high levels of SAA during chronic inflammation
may contribute to the occasional development of the potentially fatal
disease reactive amyloidosis (amyloid A (AA) amyloidosis). In AA amyloidosis,
AA, an N-terminal (1–76)
fragment of SAA, frequently is found to form amyloid deposits in
the liver, kidney, and spleen. However, the presence, in vivo,
of full-length SAA in amyloid deposits and the ability of various
SAA isoforms to form fibrils
in vitro
suggest that proteolytic cleavage may not be a prerequisite for
AA deposition but rather a postdeposition event. Of the three loci
that express SAA in humans, SAA1 is the major, although not the
only, precursor of AA deposits. Similarly, type A (i.e., BALB_c)
mice contain two SAA isoforms, SAA2.1 and SAA1.1 (formerly known as SAA1
and SAA2, respectively), of which only the latter deposits into amyloid
after chronic inflammation induced with casein or azocasein. In contrast,
the CE_J mouse strain produces a single SAA isoform, SAA2.2 (formerly
known as SAA CE_J), which is amyloid-resistant. Although the exact in
vivo functions
of SAA are still obscure, its high conservation from fish to humans,
wide expression profile in tissues/cells, and dramatic increase
in expression levels during the acute phase response suggest a
fundamental protective role for SAA. Yet, despite its small size
(12 kDa) and highly significant functions, there is very limited structural
information about SAA because of its inherent poor solubility in
the apolipoprotein form. It is intriguing to understand how such a small
protein is able to mediate or directly carry out such a wide range
of functions related to inflammatory reaction and other host defense
mechanisms. The various functions of SAA may be modulated by factors
such as conformational changes induced by ligand binding or by the ability
to adopt more than one oligomeric state. Deciphering the molecular basis
of the functional and potentially pathological properties of SAA will
require understanding its structure under various conditions. In collaboration
with Wilfredo Colón
(Rensselaer Polytechnic Institute), we showed by various methods
that murine SAA2.2 can exist in aqueous solution as a hexamer containing
a putative central channel.
)
Electron micrographs of SAA2.2 specimens showed particles with a diameter
of ~8 nm that were quite homogeneous in size and appearance. Even in the
raw images a stain accumulation in the center of the doughnut-shaped particles
was evident, suggesting the presence of a central cavity or a putative
pore. Averages obtained by classification showed few features other than
a central stain accumulation, the putative pore, with a diameter of ~2.5
nm (first two averages). The lack of fine structure in the averages is
not surprising considering the very small size of the particles. Nevertheless,
one of the class averages showed indications of the ring being composed
of six subunits (third average). This average was therefore six-fold symmetrized
(fourth average). Occasionally, bright spots could be seen in the raw
images (indicated by circles) that might represent monomeric SAA2.2.
 » Wang et
al. (2002) Proc. Natl. Acad. Sci. USA 99:
15947-15952. |