DE loop mutations affect β2-microglobulin stability and amyloid aggregation

Ricagno, Stéfano; Colombo, Matteo; Rosa, Matteo de; Sangiovanni, Enrico; Giorgetti, Sofia; Raimondi, Sara; Bellotti, Vittorio; Bolognesi, Martino

doi:10.1016/j.bbrc.2008.09.108

Cited by 37 publications

(71 citation statements)

References 25 publications

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“…Thermal unfolding of tertiary structures monitored by near-UV CD [ Fig. 2(A)] is in complete accord with previous results, [21][22][23] showing that the W60G mutation substantially increases thermal stability of the b2m fold (T m shift of about þ8 C). On the opposite, the W60V mutation does not have any measurable effect on the T m (Table I).…”

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confidence: 79%

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DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

et al. 2010

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b2 microglobulin (b2m) is the light chain of class-I major histocompatibility complex (MHC-I). Its accumulation in the blood of patients affected by kidney failure leads to amyloid deposition around skeletal joints and bones, a severe condition known as Dialysis Related Amyloidosis (DRA). In an effort to dissect the structural determinants of b2m aggregation, several b2m mutants have been previously studied. Among these, three single-residue mutations in the loop connecting strands D and E (W60G, W60V, D59P) have been shown to affect b2m amyloidogenic properties, and are here considered. To investigate the biochemical and biophysical properties of wild-type (w.t.) b2m and the three mutants, we explored thermal unfolding by Trp fluorescence and circular dichroism (CD). The W60G mutant reveals a pronounced increase in conformational stability. Protein oligomerization and reduction kinetics were investigated by electrospray-ionization mass spectrometry (ESI-MS). All the mutations analyzed here reduce the protein propensity to form soluble oligomers, suggesting a role for the DE-loop in intermolecular interactions. A partially folded intermediate, which may be involved in protein aggregation induced by acids, accumulates for all the tested proteins at pH 2.5 under oxidizing conditions. Moreover, the kinetics of disulfide reduction reveals specific differences among the tested mutants. Thus, b2m DE-loop mutations display long-range effects, affecting stability and structural properties of the native protein and its low-pH intermediate. The evidence presented here hints to a crucial role played by the DE-loop in determining the overall properties of native and partially folded b2m.

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confidence: 79%

“…Accordingly, the D59P mutation increases the loop rigidity, resulting in lower stability and higher tendency to aggregation. 22 The W60V mutant showed the same stability of w.t. b2m to chemical denaturants, but reduced amyloidogenic propensity under mild conditions.…”

Section: Introductionmentioning

confidence: 97%

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

et al. 2010

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“…13,10 MD results highlight that DE loop in D59P exhibit more conformational flexibility as compare to wt β2m. To investigate the enhanced fluctuations in DE loop region, Ser57-Ser61, the number of hydrogen bonds were evaluated ( Table 2).…”

Section: De Loop (Ser57-ser61)mentioning

confidence: 94%

“…10,11 A large number of β2m mutants have been investigated for their amyloidogenic propensities. [10][11][12][13][14][15] The local dynamics of the region spanning the strand D and DE loop, which establishes contacts with the MHC-I heavy chain have been reported to play a key role in β2m fibrillogenesis. 16 The DE loop region is a key structural element of the β2m protein.…”

Section: Introductionmentioning

confidence: 99%

“…20 The D59P mutation in the DE loop region results in the increased aggregation propensity of the mutant structure as compare to wt β2m. 13 The authors reported that D59P variant increases strain in the DE loop region, reduces protein stability and hence display an increased potential to form fibrils. However, the molecular mechanism behind the observed enhanced tendency of D59P to form amyloid aggregates is still not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2‐microglobulin: A molecular dynamics simulation study

Narang

Shuaib

Goyal

2017

J of Cellular Biochemistry

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Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic β2-microglobulin (β2m) protein around skeletal joints and bones. The recent studies highlighted a critical role of the DE loop region for β2m stability and amyloid aggregation propensity. Despite significant efforts, the molecular mechanism of enhanced aggregation due to D59P mutation in the DE loop region remain elusive. In the present study, explicit-solvent molecular dynamics (MD) simulations were performed to examine the key changes in the structural and dynamic properties of wild type (wt) β2m upon D59P mutation. MD simulations reveal a decrease in the average number of hydrogen bonds in the loop regions on D59P mutation that enhances conformational flexibility, which lead to higher aggregation propensity of D59P as compare to wt β2m. The principal component analysis (PCA) highlight that D59P covers a larger region of phase space and display a higher trace value than wt β2m, which suggest an overall enhancement in the conformational flexibility. D59P display two minimum energy basins in the free energy landscape (FEL) that are associated with thermodynamically less stable conformational states as compare to single minimum energy basin in wt β2m. The present study provides theoretical insights into the molecular mechanism behind the higher aggregation propensity of D59P as compare to wt β2m. K E Y W O R D Samyloid aggregation, β2-microglobulin, D59P mutation, DE loop, molecular dynamics

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Amyloid fibrils act as a reservoir of soluble oligomers, the main culprits in protein deposition diseases

et al. 2022

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Amyloid fibril formation plays a central role in the pathogenesis of a number of neurodegenerative diseases, including Alzheimer and Parkinson diseases. Transient prefibrillar oligomers forming during the aggregation process, exhibiting a small size and a large hydrophobic surface, can aberrantly interact with a number of molecular targets on neurons, including the lipid bilayer of plasma membranes, resulting in a fatal outcome for the cells. By contrast, the mature fibrils, despite presenting generally a high hydrophobic surface, are endowed with a low diffusion rate and poorly penetrate the interior of the lipid bilayer. However, increasing evidence shows that both intracellular α-synuclein fibrils, as well and as extracellular amyloid-β and β2-microglobulin fibrils, can release oligomers over time that quickly diffuse to reach the membrane of the neighboring cells. The persistent leakage of harmful oligomers from fibrils triggers an ongoing cascade of events resulting in a sustained injury to neurons and glia and also provides aggregates with the ability to cross biological membranes and diffuse between cells or cellular compartments.

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DE loop mutations affect β2-microglobulin stability and amyloid aggregation

Cited by 37 publications

References 25 publications

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2‐microglobulin: A molecular dynamics simulation study

Amyloid fibrils act as a reservoir of soluble oligomers, the main culprits in protein deposition diseases

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