scholarly journals The Crystal Structure of the C-Terminal Truncated Apolipoprotein A-I Sheds New Light on Amyloid Formation by the N-Terminal Fragment

Biochemistry ◽  
2011 ◽  
Vol 51 (1) ◽  
pp. 10-18 ◽  
Author(s):  
Olga Gursky ◽  
Xiaohu Mei ◽  
David Atkinson
Keyword(s):  
Crystal Structure ◽  
Amyloid Formation ◽  
Apolipoprotein A ◽  
Terminal Fragment

Abstract 539: Soluble Oxidized Apolipoprotein A-I, a Precursor of Amyloid Fibrils, Activates Secretion of Inflammatory Cytokines in Macrophages

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Andrzej Witkowski ◽  
Gary K Chan ◽  
Nancy J Li ◽  
Rui Lu ◽  
Shinji Yokoyama ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Amyloid Fibrils ◽  
Mouse Bone Marrow ◽  
Amyloid Formation ◽  
Cellular Cholesterol ◽  
Atherosclerosis Progression ◽  
Apolipoprotein A ◽  
Inflammatory Protein ◽  
Release Capacity

Atherosclerosis is often described as an inflammatory disease of the arteries. One mechanism whereby apolipoprotein A-I (apoA-I) exerts its anti-atherosclerotic effect is by mitigating the inflammatory response of cells involved in atherosclerosis progression. However, oxidation transforms apoA-I from an anti-inflammatory to a pro-inflammatory protein. We previously reported that oxidation can also promote apoA-I aggregation and formation of amyloid fibrils. In this study, we investigated the mechanistic interplay between oxidation, amyloid formation and the inflammatory response of macrophages to apoA-I. We hypothesized that amyloid fibrils constituted of oxidized apoA-I activate production of inflammatory cytokines in macrophages. To test this hypothesis, amyloidogenic apoA-I was generated by oxidation with an excess of H 2 O 2 (H 2 O 2 -ApoA-I). Intracellular and secreted levels of IL-1β were determined upon incubation of mouse bone marrow derived macrophages (BMDM) with intact-apoA-I, soluble H 2 O 2 -ApoA-I and pre-formed H 2 O 2 -ApoA-I amyloid fibrils. Cellular cholesterol release from RAW264.7 cells was also measured. Soluble H 2 O 2 -ApoA-I (amyloid precursor) retained the cellular cholesterol release capacity of intact-ApoA-I. In BMDM incubated with soluble H 2 O 2 -ApoA-I however, levels of IL-1β synthesis and secretion were at least 2-fold higher than those induced by intact-ApoA-I. In contrast, incubation with H 2 O 2 -ApoA-I amyloid fibrils did not increase the levels of IL-1β synthesis and secretion, compared to intact-ApoA-I. Thus, soluble and functional oxidized apoA-I activates inflammatory cytokine synthesis and secretion in macrophages. Notably, this pro-inflammatory potential was completely neutralized when oxidized apoA-I was aggregated in amyloids. Therefore in atherosclerotic lesions, amyloid formation could reduce, rather than exacerbate, the inflammatory burden produced by pro-inflammatory soluble oxidized apoA-I species.

scholarly journals High-resolution crystal structure of apolipoprotein(a) kringle IV type 7: Insights into ligand binding

2001 ◽  
Vol 10 (6) ◽  
pp. 1124-1129 ◽  
Author(s):  
Qilu Ye ◽  
Mona N. Rahman ◽  
Marlys L. Koschinsky ◽  
Zongchao Jia
Keyword(s):  
Crystal Structure ◽  
High Resolution ◽  
Ligand Binding ◽  
Apolipoprotein A

scholarly journals 1P145 The Crystal Structure of C-terminal Fragment of Rabbit Skeletal a-Tropomyosin

2005 ◽  
Vol 45 (supplement) ◽  
pp. S68
Author(s):  
Y. Nitanai ◽  
K. Maeda ◽  
N. Oda ◽  
S. Minakata ◽  
Y. Maeda
Keyword(s):  
Crystal Structure ◽  
Terminal Fragment

Crystal structure of an N-terminal fragment of the DNA gyrase B protein

Nature ◽  
1991 ◽  
Vol 351 (6328) ◽  
pp. 624-629 ◽  
Author(s):  
Dale B. Wigley ◽  
Gideon J. Davies ◽  
Eleanor J. Dodson ◽  
Anthony Maxwell ◽  
Guy Dodson
Keyword(s):  
Crystal Structure ◽  
Dna Gyrase ◽  
Terminal Fragment

Heparin promotes fibril formation by the N-terminal fragment of amyloidogenic apolipoprotein A-I

FEBS Letters ◽  
2016 ◽  
Vol 590 (20) ◽  
pp. 3492-3500 ◽  
Author(s):  
Shiho Mikawa ◽  
Chiharu Mizuguchi ◽  
Kazuchika Nishitsuji ◽  
Teruhiko Baba ◽  
Akira Shigenaga ◽  
...  
Keyword(s):  
Fibril Formation ◽  
Apolipoprotein A ◽  
Terminal Fragment

scholarly journals The Alzheimer β-amyloid protein precursor/protease nexin-II is cleaved by secretase in a trans-Golgi secretory compartment in human neuroglioma cells

1993 ◽  
Vol 295 (2) ◽  
pp. 367-378 ◽  
Author(s):  
S L Kuentzel ◽  
S M Ali ◽  
R A Altman ◽  
B D Greenberg ◽  
T J Raub
Keyword(s):  
Plasma Membrane ◽  
Beta Amyloid ◽  
Full Length ◽  
Amyloid Formation ◽  
Amyloid Protein ◽  
Extracellular Medium ◽  
Protein Precursor ◽  
Amyloid Protein Precursor ◽  
Terminal Fragment ◽  
Golgi Compartment

Alzheimer beta-amyloid protein precursor (beta APP) is expressed endogenously and abundantly by human neuroglioma (H4) cells. Its secretory processing has been shown to involve discrete proteolysis within the beta A4 region, thus preventing beta-amyloid formation, by an enzyme which has been referred to as ‘beta APP secretase’. This cleavage results in secretion of a soluble N-terminal 135 kDa protein and retention of an integral membrane C-terminal fragment within the cell. The membrane-associated C-terminal fragment is sorted to lysosomes where it undergoes limited degradation. We show here that most newly synthesized beta APP is degraded via a non-lysosomal pathway before maturation in H4 cells, and most mature beta APP is processed predominantly by the so-called secretase. The rapid kinetics of appearance/disappearance of a cleaved 135 kDa protein within a microsomal fraction and the slow accumulation of this form in the extracellular medium indicated that secretase cleaves beta APP in an intracellular compartment. Low-temperature block (20 degrees C) was used to demonstrate that beta APP is cleaved within a late Golgi compartment after sulphation which occurs in the trans-Golgi network (TGN). This is consistent with (1) the immunolocalization of most of the beta APP within a Golgi compartment that reacts with wheat germ agglutinin, (2) the fact that less than 1.5% of the total mature full-length beta APP is present at the plasma membrane and (3) subcellular fractionation studies which showed that the mature full-length and intracellular cleaved beta APPs co-sediment with a membrane fraction that is slightly more dense than the plasma membrane. This study provides evidence that most of the beta APP secretase in H4 cells is intracellular, and confirms that the resulting C-terminal fragment is delivered to lysosomes immediately after cleavage. These results are discussed with regard to the possibility that mature full-length beta APP escapes secretase cleavage and is delivered directly from the TGN to the lysosome without passing through the plasma membrane. Either pathway will result in the generation of amyloidogenic fragments.

scholarly journals Crystal structure of truncated human apolipoprotein A-I suggests a lipid-bound conformation

1997 ◽  
Vol 94 (23) ◽  
pp. 12291-12296 ◽  
Author(s):  
D. W. Borhani ◽  
D. P. Rogers ◽  
J. A. Engler ◽  
C. G. Brouillette
Keyword(s):  
Crystal Structure ◽  
Human Apolipoprotein ◽  
Apolipoprotein A

scholarly journals Amyloidogenic Mutation Promotes Fibril Formation of the N-terminal Apolipoprotein A-I on Lipid Membranes

2015 ◽  
Vol 290 (34) ◽  
pp. 20947-20959 ◽  
Author(s):  
Chiharu Mizuguchi ◽  
Fuka Ogata ◽  
Shiho Mikawa ◽  
Kohei Tsuji ◽  
Teruhiko Baba ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Amyloid Fibrils ◽  
Helical Structure ◽  
Lipid Binding ◽  
Fibril Formation ◽  
Random Coil ◽  
Helical Conformation ◽  
Apolipoprotein A ◽  
Terminal Fragment ◽  
Lipid Environment

The N-terminal amino acid 1–83 fragment of apolipoprotein A-I (apoA-I) has a strong propensity to form amyloid fibrils at physiological neutral pH. Because apoA-I has an ability to bind to lipid membranes, we examined the effects of the lipid environment on fibril-forming properties of the N-terminal fragment of apoA-I variants. Thioflavin T fluorescence assay as well as fluorescence and transmission microscopies revealed that upon lipid binding, fibril formation by apoA-I 1–83 is strongly inhibited, whereas the G26R mutant still retains the ability to form fibrils. Such distinct effects of lipid binding on fibril formation were also observed for the amyloidogenic prone region-containing peptides, apoA-I 8–33 and 8–33/G26R. This amyloidogenic region shifts from random coil to α-helical structure upon lipid binding. The G26R mutation appears to prevent this helix transition because lower helical propensity and more solvent-exposed conformation of the G26R variant upon lipid binding were observed in the apoA-I 1–83 fragment and 8–33 peptide. With a partially α-helical conformation induced by the presence of 2,2,2-trifluoroethanol, fibril formation by apoA-I 1–83 was strongly inhibited, whereas the G26R variant can form amyloid fibrils. These findings suggest a new possible pathway for amyloid fibril formation by the N-terminal fragment of apoA-I variants: the amyloidogenic mutations partially destabilize the α-helical structure formed upon association with lipid membranes, resulting in physiologically relevant conformations that allow fibril formation.

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