Effect of amino acid mutations on the conformational dynamics of amyloidogenic immunoglobulin light-chains: A combined NMR and in silico study

Mukherjee, Sujoy; Pondaven, Simon P.; Hand, Kieran; Madine, Jillian; Jaroniec, Christopher P.

doi:10.1038/s41598-017-10906-w

Cited by 7 publications

(4 citation statements)

References 51 publications

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“…In the case of endogenous proteins synthesized in the ER, we found the recognition motif in the edge strand of certain Ig domains, including those of antibodies. Uniformly, the motif located to regions of Ig domains that are dynamic and relatively unstable (44,45). And given the sheet topology of Ig domains (Fig.…”

Section: Implications For Sensing Misfolded Proteins By Ire1αmentioning

confidence: 99%

Structural basis for recognition of unfolded proteins by the ER stress sensor ERN1/IRE1α

Simpson,

Luca,

Cauthorn

et al. 2023

Preprint

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IRE1α is an endoplasmic reticulum sensor that recognizes misfolded proteins to activate the unfolded protein response (UPR). We used cholera toxin (CTx), which activates IRE1α in cells, to understand how unfolded proteins are recognized. In vitro, the A1 subunit of CTx (CTxA1) bound IRE1α lumenal domain (IRE1αLD). Global unfolding was not required. Instead, IRE1αLDrecognized a 7-residue motif within a metastable region of CTxA1 that was also found in microbial and host proteins involved in IRE1α activation. Binding mapped to a pocket on IRE1αLDnormally occupied by a segment of the IRE1α C-terminal flexible loop implicated in IRE1α regulation. Mutation of the recognition motif blocked CTx-induced IRE1α activation in live cells. These findings describe a mechanism for substrate recognition by IRE1α that induces the UPR.

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Section: Implications For Sensing Misfolded Proteins By Ire1αmentioning

confidence: 99%

Structural basis for recognition of unfolded proteins by the ER stress sensor ERN1/IRE1α

Simpson,

Luca,

Cauthorn

et al. 2023

Preprint

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“…45,90 As recently reported, increasing the conformational flexibility of the LC, regardless of the impact on its thermodynamic of folding, is another way by which somatic mutations can promote amyloid aggregation. 91,92 It has also been found that somatic mutations that disrupt the LC dimer interface and shift the equilibrium toward the less thermodynamically stable monomeric LC, have the potential to favor amyloidogenesis. 84,93,94 Because association into a stable dimer protects LC from aggregation, 89,[94][95][96][97] pharmacologic stabilization the LC dimer has been proposed as an potential therapeutic strategy for AL-Am amyloidosis.…”

Section: Contribution Of the Somatic Mutationsmentioning

confidence: 99%

Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease

Herrera

Teng

Turbat‐Herrera

et al. 2020

Kidney International Reports

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Patients with plasma cell dyscrasias produce free abnormal monoclonal Ig light chains that circulate in the blood stream. Some of them, termed glomerulopathic light chains, interact with the mesangial cells and trigger, in a manner dependent of their structural and physicochemical properties, a sequence of pathological events that results in either light chain-derived (AL) amyloidosis (AL-Am) or light chain deposition disease (LCDD). The mesangial cells play a key role in the pathogenesis of both diseases. The interaction with the pathogenic light chain elicits specific cellular processes, which include apoptosis, phenotype transformation, and secretion of extracellular matrix components and metalloproteinases. Monoclonal light chains associated with AL-Am but not those producing LCDD are avidly endocytosed by mesangial cells and delivered to the mature lysosomal compartment where amyloid fibrils are formed. Light chains from patients with LCDD exert their pathogenic signaling effect at the cell surface of mesangial cells. These events are generic mesangial responses to a variety of adverse stimuli, and they are similar to those characterizing other more frequent glomerulopathies responsible for many cases of end-stage renal disease. The pathophysiologic events that have been elucidated allow to propose future therapeutic approaches aimed at preventing, stopping, ameliorating, or reversing the adverse effects resulting from the interactions between glomerulopathic light chains and mesangium.

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“…Various molecular properties of the light chains, such as thermal stability [9,[14][15][16][16][17][18][19] tendency to dimerize [20][21][22] and the dimer interface [23], or protein dynamics [14,24], have been proposed to correlate with their deposition as amyloid fibrils. However, some findings are contradictory, for instance the reports that dimeric LCs are more often found in AL patients [20,22] versus those that the monomeric state is more critical for fibril formation [21] and that stable dimers can even inhibit the aggregation [25].…”

Section: Introductionmentioning

confidence: 99%

Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains

et al. 2023

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Background In a range of human disorders such as multiple myeloma (MM), immunoglobulin light chains (IgLCs) can be produced at very high concentrations. This can lead to pathological aggregation and deposition of IgLCs in different tissues, which in turn leads to severe and potentially fatal organ damage. However, IgLCs can also be highly soluble and non-toxic. It is generally thought that the cause for this differential solubility behaviour is solely found within the IgLC amino acid sequences, and a variety of individual sequence-related biophysical properties (e.g. thermal stability, dimerisation) have been proposed in different studies as major determinants of the aggregation in vivo. Here, we investigate biophysical properties underlying IgLC amyloidogenicity. Results We introduce a novel and systematic workflow, Thermodynamic and Aggregation Fingerprinting (ThAgg-Fip), for detailed biophysical characterisation, and apply it to nine different MM patient-derived IgLCs. Our set of pathogenic IgLCs spans the entire range of values in those parameters previously proposed to define in vivo amyloidogenicity; however, none actually forms amyloid in patients. Even more surprisingly, we were able to show that all our IgLCs are able to form amyloid fibrils readily in vitro under the influence of proteolytic cleavage by co-purified cathepsins. Conclusions We show that (I) in vivo aggregation behaviour is unlikely to be mechanistically linked to any single biophysical or biochemical parameter and (II) amyloidogenic potential is widespread in IgLC sequences and is not confined to those sequences that form amyloid fibrils in patients. Our findings suggest that protein sequence, environmental conditions and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.

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Effect of amino acid mutations on the conformational dynamics of amyloidogenic immunoglobulin light-chains: A combined NMR and in silico study

Cited by 7 publications

References 51 publications

Structural basis for recognition of unfolded proteins by the ER stress sensor ERN1/IRE1α

Structural basis for recognition of unfolded proteins by the ER stress sensor ERN1/IRE1α

Understanding Mesangial Pathobiology in AL-Amyloidosis and Monoclonal Ig Light Chain Deposition Disease

Widespread amyloidogenicity potential of multiple myeloma patient-derived immunoglobulin light chains

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