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Serum Amyloid a Forms Stable Oligomers That Disrupt Vesicles At Serum amyloid A forms stable oligomers that disrupt PNAS PLUS vesicles at lysosomal pH and contribute to the pathogenesis of reactive amyloidosis Shobini Jayaramana,1, Donald L. Gantza, Christian Hauptb, and Olga Gurskya aDepartment of Physiology & Biophysics, Boston University School of Medicine, Boston, MA 02118; and bInstitute of Protein Biochemistry, University of Ulm, 89081 Ulm, Germany Edited by Susan Marqusee, University of California, Berkeley, CA, and approved June 29, 2017 (received for review April 28, 2017) Serum amyloid A (SAA) is an acute-phase plasma protein that functions prefibrillar oligomers with diverse structural and pathogenic fea- in innate immunity and lipid homeostasis. SAA is a protein precursor of tures (see refs. 13–15 and references therein). Such polymorphic reactive AA amyloidosis, the major complication of chronic inflamma- oligomers can exert toxicity through multiple mechanisms in- tion and one of the most common human systemic amyloid diseases cluding perforation of cell membranes (7, 13); in addition, mature worldwide. Most circulating SAA is protected from proteolysis and fibrils can mediate a range of pathological processes (16, 17). misfolding by binding to plasma high-density lipoproteins. However, Certain “on-path” oligomers can also trigger fibril formation via unbound soluble SAA is intrinsically disordered and is either rapidly the crystallization-like nucleation-growth mechanism (16, 18) in a degraded or forms amyloid in a lysosome-initiated process. Although process that can be affected by cell membranes. acidic pH promotes amyloid fibril formation by this and many other Unlike neurodegenerative disorders such as Alzheimer’s, in proteins, the molecular underpinnings are unclear. We used an array of AA amyloidosis, fibril removal restores organ function, which spectroscopic, biochemical, and structural methods to uncover that at suggests that AA fibrils per se are pathogenic and sets the basis pH 3.5–4.5, murine SAA1 forms stable soluble oligomers that are max- for the current treatment of AA amyloidosis (4, 5, 19, 20). imally folded at pH 4.3 with ∼35% α-helix and are unusually resistant Nevertheless, small soluble SAA-based oligomers can also con- to proteolysis. In solution, these oligomers neither readily convert into tribute to the AA pathogenesis (21–24). Clinically, once AA deposits mature fibrils nor bind lipid surfaces via their amphipathic α-helices in a have been cleared by administering anti-inflammatory therapies to manner typical of apolipoproteins. Rather, these oligomers undergo an decrease the plasma levels of SAA, new fibrils form again much α-helix to β-sheet conversion catalyzed by lipid vesicles and disrupt faster on repeated exposure to inflammatory stimuli that up-regulate these vesicles, suggesting a membranolytic potential. Our results pro- SAA (18–20). Such a recurring amyloidosis is probably triggered vide an explanation for the lysosomal origin of AA amyloidosis. They by particularly stable SAA-derived species that cannot be com- suggest that high structural stability and resistance to proteolysis of pletely eliminated by therapeutic interventions. These species – SAA oligomers at pH 3.5 4.5 help them escape lysosomal degradation, are perhaps akin to the amyloid-enhancing factor (AEF) derived promote SAA accumulation in lysosomes, and ultimately damage cel- from amyloid deposits in vivo, which can nucleate fibril forma- lular membranes and liberate intracellular amyloid. We posit that these tion in vitro (21, 22). Oral administration of AEF can induce AA soluble prefibrillar oligomers provide a missing link in our understand- amyloidosis in mice, indicating prion-like transmission (18, 25). A ingofthedevelopmentofAAamyloidosis. hallmark of such a transmission is the high stability of prions, which confers resistance to denaturation and proteolytic degradation in prefibrillar amyloid oligomers | intrinsically disordered proteins | the digestive tract. Therefore, high stability of SAA-based AEF is pH-induced conformational changes | hydrophobic cavities | probably important for the onset of AA amyloidosis in humans and acute-phase reactant Significance erum amyloid A (SAA, 12 kDa) is an intrinsically disordered plasma protein that functions in innate immunity and lipid S Although acidic conditions favor the misfolding of various proteins homeostasis and is up-regulated in inflammation (1–3). Most in amyloid diseases, the molecular underpinnings of this process circulating SAA binds to its major plasma carrier, high-density are unclear. We used an array of spectroscopic, biochemical, and lipoprotein (HDL), and thereby reroutes HDL transport and electron microscopic methods to unravel the effects of pH on se- promotes lipid clearance from the sites of injury and lipid recycling rum amyloid A, a protein precursor of reactive amyloidosis, the for tissue repair (2, 3). Binding to HDL stabilizes the α-helical major complication of chronic inflammation and one of the major BIOCHEMISTRY structure in SAA and protects it from proteolysis and misfolding. human systemic amyloidoses worldwide. We found that at lyso- Such a misfolding underlies amyloid A (AA) amyloidosis, a major somal pH this protein forms unusually stable proteolysis-resistant complication of chronic inflammation and a common form of soluble oligomers that have solvent-accessible apolar surfaces, human systemic amyloidosis (4, 5). In this life-threatening disease, disrupt lipid vesicles, and undergo an α-helix to β-sheet transition N-terminal fragments of SAA, termed AA, deposit as fibrils in in the presence of lipids. Such oligomers are likely to escape ly- kidneys, spleen, and other organs, causing organ damage (4–6). sosomal degradation, accumulate in the lysosomes, and disrupt Although binding to the lipid surface mediates normal functions cellular membranes, thereby contributing to the development of of SAA in lipid transport, SAA interactions with cell membranes BIOPHYSICS AND amyloid A amyloidosis. may also modulate pathologic effects in AA amyloidosis (7, 8). Molecular underpinnings for these effects are beginning to be COMPUTATIONAL BIOLOGY Author contributions: S.J. designed research; S.J. and D.L.G. performed research; C.H. elucidated (9) and are explored in the current study. contributed new reagents/analytic tools; S.J. and O.G. analyzed data; and S.J. and O.G. Aberrant interactions of amyloidogenic proteins with cell mem- wrote the paper. branes have been implicated in the pathogenesis of other amyloid The authors declare no conflict of interest. diseases such as Alzheimer’s, Parkinson’s, type 2 diabetes, etc. (see This article is a PNAS Direct Submission. – refs. 10 12 and references therein). Furthermore, extensive evi- 1To whom correspondence should be addressed. Email: [email protected]. dence suggests that the primary cytotoxic species in various forms of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. systemic and neurodegenerative amyloidoses are compact soluble 1073/pnas.1707120114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1707120114 PNAS | Published online July 25, 2017 | E6507–E6515 Downloaded by guest on September 25, 2021 its transmission in mice. The molecular entity responsible for the such a pH-dependent structural transition in SAA has not been AEF activity in AA amyloidosis is unclear and was proposed to previously reported. comprise degradation-resistant species, including prefibrillar dif- The temperature dependence of the secondary structure at var- fusible oligomers or small fibril fragments (23, 25). Here we de- ious pH was monitored by CD at 210 nm during protein heating scribe soluble SAA oligomers formed at lysosomal pH in vitro, and cooling at a constant rate (Fig. 1B). At pH 7.5, SAA was which have unusually high stability, disrupt lipid vesicles, and partially α-helical at 5 °C and showed reversible thermal unfolding hence may contribute to the SAA accumulation in the cells, cell with a midpoint Tm = 18 °C. At pH 3.0, SAA was also substantially membrane damage, and AA pathogenesis. α-helical at 5 °C and unfolded reversibly with a Tm = 18 °C. Un- Acidic pH, particularly in the lysosomal or endosomal com- expectedly, at pH 4.3 the unfolding shifted to much higher tem- – partment (pH 4.5 5.5), is well-known to favor fibril formation in peratures (Tm = 50 °C) and became thermodynamically irreversible, vivo and in vitro by many protein precursors of major human with a large hysteresis in the melting data (Fig. 1B). Such a hys- amyloidoses, including SAA, transthyretin, Ig light chain, Aβ pep- teresis is typical of lipid-bound but not lipid-free apolipoproteins, tide,etc.(seeref.26andreferences therein). In vitro fibril forma- including SAA (30, 31). Irreversible unfolding of SAA at pH 4.3 tion by SAA and AA requires acidic conditions (27) that are was also evident from far-UV CD spectra recorded before and optimal circa pH 3 (9). Moreover, ex vivo and cell-based immu- after heating to 80 °C, and the difference spectrum showed an nohistochemical and electron microscopic (EM) studies have clearly irreversible loss of ordered secondary structure (Fig. 1C, Inset). established lysosomes as the initial sites of AA fibril formation in Further, the heating data of lipid-free SAA at any pH explored macrophages and other cells (26, 28, 29). Besides acidic pH, protein showed no scan rate dependence, suggesting the absence of high concentration in lysosomes and the activity of acidic proteases activation energy (30). probably
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