Mapping the Structural Transition in an Amyloidogenic Apolipoprotein A-I

Lagerstedt, Jens O.; Cavigiolio, Giorgio; Roberts, Larry E.; Hong, Hyun Seok; Jin, Lee‐Way; Fitzgerald, Paul G.; Oda, Michael N.; Voss, John C.

doi:10.1021/bi7005493

Cited by 46 publications

(74 citation statements)

References 36 publications

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“…Combined with the secondary structure examination of the apoA-I G26R variant (13) and a finding that a peptide comprising residues 46 -59 of apoA-I aggregates to form amyloid-like fibrils (72), it is considered that residues 14 -31 and 46 -59 in the apoA-I G26R variant are highly amyloidogenic regions that undergo the transition to the ␤-strand structure. Interestingly, the first amyloidogenic region overlaps with a very hydrophobic segment in the hydropathy plot (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…So far, there are about 20 known mutations in the APOA1 gene associated with hereditary systemic apoA-I amyloidosis (9,10), among which G26R, the first and most common amyloidogenic mutation (11)(12)(13), is characterized by amyloid deposits in the peripheral nerves, kidneys, liver, and gastrointestinal tract (11,14). Although the precise mechanism for the amyloidogenicity of variant apoA-I remains unclear, it is thought that an unstable N-terminal helix bundle conformation associated with amyloidogenic mutations promotes proteolytic cleavage of the full-length protein (10,15,16), which deposits in the extracellular space of target tissues (17).…”

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confidence: 99%

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

Mizuguchi

Ogata

Mikawa

et al. 2015

Journal of Biological Chemistry

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Background:The N-terminal fragment of amyloidogenic apoA-I mutants deposits as fibrils by unknown mechanisms. Results: The G26R mutation partially prevents helix formation of the N-terminal fragment upon lipid binding, thereby facilitating ␤-transition and fibril formation. Conclusion: Membrane binding modulates fibril formation of apoA-I through partially destabilized helical conformation. Significance: The results reveal a new pathway for amyloid fibril formation by apoA-I.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Mizuguchi

Ogata

Mikawa

et al. 2015

Journal of Biological Chemistry

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“…For example, the presence of a G26R mutation in apoA-I Iowa leads to unfolding of the helix spanning residues 7-44 ( Fig. 3A ) which, in turn, destabilizes the helix bundle ( 48 ); this destabilization promotes proteolysis at residue 83 and formation of amyloid ( 49 ).…”

Section: Molecular Mechanism Of Apoa-i Binding To Lipidsmentioning

confidence: 99%

New insights into the determination of HDL structure by apolipoproteins

Phillips

2013

Journal of Lipid Research

150

106

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This article is available online at http://www.jlr.orgThe purpose of this review is to summarize current understanding of how apolipoproteins (apoA-I in particular) determine the structures of HDL particles. The focus is on recent advances in the fi eld, so the coverage of the literature on HDL structure is not comprehensive. Knowledge of HDL structure at the molecular level is critical for understanding how this lipoprotein achieves the multiple functions elaborated in other reviews in this thematic series.In human plasma, HDL is a heterogeneous collection of particles ranging 7-12 nm in diameter and 1.063-1.21 g/ml in density ( 1-4 ). The predominant species of HDL are spherical microemulsion particles, in which a core of neutral cholesteryl ester (CE) and triacylglycerol (TG) is encapsulated by a monolayer of phospholipid (PL), unesterifi ed (free) cholesterol (FC), and protein ( 5 ). The protein and PL constituents comprise approximately 50 and 25%, respectively, of the mass of such particles, with the CE, FC, and TG components making up the remainder. Larger, less dense HDL particles have a higher lipidto-protein mass ratio. Approximately 70% of total plasma HDL protein is apoA-I (which is present in normolipidemic human plasma at ‫ف‬ 130 mg/dl), and it is located in essentially every HDL particle. The second most abundant protein is apoA-II, which comprises 15-20% of total plasma HDL protein, but this component is not present in all HDL particles. In human plasma, about 25% of apoA-I is present in HDL particles containing only apoA-I (LpA-I); the remaining HDL particles contain both apoA-I and apoA-II (LpA-I+A-II), typically in a molar ratio of 1-2/1 ( 6 ). ApoA-I and apoA-II are the "scaffold" proteins that primarily determine HDL particle structure. Other members of the exchangeable apolipoprotein gene family that are Abstract Apolipoprotein (apo)A-I is the principal protein component of HDL, and because of its conformational adaptability, it can stabilize all HDL subclasses. The amphipathic ␣ -helix is the structural motif that enables apoA-I to achieve this functionality. In the lipid-free state, the helical segments unfold and refold in seconds and are located in the N-terminal two thirds of the molecule where they are loosely packed as a dynamic, four-helix bundle. The C-terminal third of the protein forms an intrinsically disordered domain that mediates initial binding to phospholipid surfaces, which occurs with coupled ␣ -helix formation. The lipid affi nity of apoA-I confers detergent-like properties; it can solubilize vesicular phospholipids to create discoidal HDL particles with diameters of approximately 10 nm. Such particles contain a segment of phospholipid bilayer and are stabilized by two apoA-I molecules that are arranged in an anti-parallel, double-belt conformation around the edge of the disc, shielding the hydrophobic phospholipid acyl chains from exposure to water. The apoA-I molecules are in a highly dynamic state, and they stabilize discoidal particles of different sizes by certain s...

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“…Studies have shown that removal of the N-terminal region causes the protein to fold in alternative conformation(s) that affects its overall stability (53), whereas other studies show that removal of this region alters the proteinʼs ability to bind lipid (54). Even simple mutations in the N-terminal region, such as G26R, have been shown to cause decreased lipid binding capability (55). The C-terminal domain (helices 8 through 10) appears to promote "self-association" of apoA-I with itself (56-58) as well as to lipid (44,53).…”

Section: Lipid-bound Conformation Of Apoa-i: Helix Registry Of Two Apmentioning

confidence: 99%

Three-dimensional models of HDL apoA-I: implications for its assembly and function

Thomas

Bhat

Sorci‐Thomas

2008

Journal of Lipid Research

109

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The purpose of this review is to highlight recent advances toward the refinement of a three-dimensional structure for lipid-bound apolipoprotein A-I (apoA-I) on recombinant HDL. Recently, X-ray crystallography has yielded a new structure for full-length, lipid-free apoA-I. Although this approach has not yet been successful in solving the threedimensional structure of lipid-bound apoA-I, analysis of the X-ray structures has been of immense help in the interpretation of structural data obtained from other methods that yield structural information. Recent studies emphasize the use of mass spectrometry to unambiguously identify crosslinked peptides or to quantify solvent accessibility using hydrogen-deuterium exchange. The combination of mass spectrometry, molecular modeling, molecular dynamic analysis, and small-angle X-ray diffraction has provided additional structural information on apoA-I folding that complements previous approaches. To understand the mechanism of HDL apolipoprotein A-I (apoA-I) protection against the development of coronary heart disease, recent investigations have focused on apoA-Iʼs dual functions in promoting lipid efflux (1-4) and its role in modulating immune cell activation (5-10). Recent attention has now focused on elucidating the threedimensional conformation of apoA-I, the most abundant protein constituent within the HDL particle, in response to its acquisition of phospholipid and cholesterol to form nascent lipoprotein particles.ApoA-I is a 28 kDa protein synthesized by the liver and small intestine. It plays a key role in the formation, metabolism, and catabolism of HDL, a plasma lipoprotein whose levels are highly linked to protection against the development of coronary artery disease, even in patients with very low LDL cholesterol levels (11). Formation of plasma HDL particles depends entirely on the initial lipidation of apoA-I by ABCA1 (12-14). Dimers of lipid-free or lipid-poor apoA-I acquire limited amounts of phospholipid and cholesterol from the membrane-bound ABCA1 transporter to form one of several classes of nascent HDL particles (15). Other classes of nascent HDL particles formed from this interaction contain more than two molecules of apoA-I per particle, with increased amounts of phospholipid and cholesterol (16)(17)(18).A second lipidation step essential for plasma HDL maturation is the activation of the enzyme LCAT by lipid-bound apoA-I. Activation of this enzyme results in the synthesis of cholesteryl esters on nascent HDL (19), providing a hydrophobic core and transforming the small, lipid-poor particle to a spherical lipid-rich HDL. Studies of human deficiencies have shown that if either ABCA1 or LCAT are inactive, plasma concentrations of HDL apoA-I are very low, owing to the rapid removal of the small lipid-poor HDL apoA-I from circulation (20,21). Thus, both of these two major apoA-I lipidation steps are absolutely essential for the formation of mature spherical plasma HDL and, to some extent, the functionality of the HDLs themselves (22-24).ApoA-I has...

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Mapping the Structural Transition in an Amyloidogenic Apolipoprotein A-I

Cited by 46 publications

References 36 publications

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

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

New insights into the determination of HDL structure by apolipoproteins

Three-dimensional models of HDL apoA-I: implications for its assembly and function

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