Advanced lipoxidation end products (ALEs) as RAGE binders: Mass spectrometric and computational studies to explain the reasons why

Mol, Marco; Degani, Genny; Coppa, Crescenzo; Baron, Giovanna; Popolo, Laura; Carini, Marina; Vistoli, Giulio; Altomare, Alessandra

doi:10.1016/j.redox.2018.101083

Cited by 35 publications

(39 citation statements)

References 34 publications

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“…Indeed, lipoxidized proteins are ligands for the receptor for advanced glycated end products (RAGE), which has been involved in the pathogenic consequences of hyperglycemia or inflammation. By abolishing the positive charges of lysine residues, lipoxidation disrupts the ion pairs with negative residues in their vicinity, enabling the latter to interact with positive residues in RAGE, favoring the activation of this receptor [ 118 ]. Through this mechanism, lipoxidized proteins could contribute to propagate the damage.…”

Section: Vimentinmentioning

confidence: 99%

Type III intermediate filaments as targets and effectors of electrophiles and oxidants

Viedma-Poyatos

Pajares

2020

Redox Biology

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Intermediate filaments (IFs) play key roles in cell mechanics, signaling and homeostasis. Their assembly and dynamics are finely regulated by posttranslational modifications. The type III IFs, vimentin, desmin, peripherin and glial fibrillary acidic protein (GFAP), are targets for diverse modifications by oxidants and electrophiles, for which their conserved cysteine residue emerges as a hot spot. Pathophysiological examples of these modifications include lipoxidation in cell senescence and rheumatoid arthritis, disulfide formation in cataracts and nitrosation in endothelial shear stress, although some oxidative modifications can also be detected under basal conditions. We previously proposed that cysteine residues of vimentin and GFAP act as sensors for oxidative and electrophilic stress, and as hinges influencing filament assembly. Accumulating evidence indicates that the structurally diverse cysteine modifications, either per se or in combination with other posttranslational modifications, elicit specific functional outcomes inducing distinct assemblies or network rearrangements, including filament stabilization, bundling or fragmentation. Cysteine-deficient mutants are protected from these alterations but show compromised cellular performance in network assembly and expansion, organelle positioning and aggresome formation, revealing the importance of this residue. Therefore, the high susceptibility to modification of the conserved cysteine of type III IFs and its cornerstone position in filament architecture sustains their role in redox sensing and integration of cellular responses. This has deep pathophysiological implications and supports the potential of this residue as a drug target.

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Section: Vimentinmentioning

confidence: 99%

Type III intermediate filaments as targets and effectors of electrophiles and oxidants

Viedma-Poyatos

Pajares

2020

Redox Biology

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“…Thus, MDALys formation induces alterations in physico-chemical properties such as conformation [ 5 ], charge [ 73 ], and solubility [ 48 ], formation of intra- and inter-molecular protein cross-links and aggregates [ 11 , 48 , 51 ], loss of enzymatic activity [ 15 , 47 ], and accelerated rate (for MDALys) or resistance to proteolysis (cross-links) [ 69 ]. When biological effects are considered, deleterious consequences such as immunogenicity (MDA generates immunoreactive materials in proteins) [ 43 , 51 ], binder to the receptor for advanced glycation end-products (RAGE) [ 73 ], and induction of monocyte activation and vascular complications [ 74 ] have been described. Additionally, MDA-adducts formation on nucleic acids induces DNA damage and mutagenesis [ 27 , 28 , 29 ], as well as alterations in physico-chemical and biological properties of the lipid bilayer when aminophospholipids are modified [ 30 ].…”

Section: Cytotoxic Effects Of Mdalys Adductsmentioning

confidence: 99%

The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity

et al. 2020

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The nonenzymatic adduction of malondialdehyde (MDA) to the protein amino groups leads to the formation of malondialdehyde-lysine (MDALys). The degree of unsaturation of biological membranes and the intracellular oxidative conditions are the main factors that modulate MDALys formation. The low concentration of this modification in the different cellular components, found in a wide diversity of tissues and animal species, is indicative of the presence of a complex network of cellular protection mechanisms that avoid its cytotoxic effects. In this review, we will focus on the chemistry of this lipoxidation-derived protein modification, the specificity of MDALys formation in proteins, the methodology used for its detection and quantification, the MDA-lipoxidized proteome, the metabolism of MDA-modified proteins, and the detrimental effects of this protein modification. We also propose that MDALys is an indicator of the rate of aging based on findings which demonstrate that (i) MDALys accumulates in tissues with age, (ii) the lower the concentration of MDALys the greater the longevity of the animal species, and (iii) its concentration is attenuated by anti-aging nutritional and pharmacological interventions.

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“…Finally, to verify whether AGE modifications contributed to the binding of the interactors to VC1, we searched for the presence of AGE/ALE (advanced lipoxidation end products) modifications in the identified proteins. No AGE or ALE modifications were detected by MS using a previously described search method (26,32) (see Discussion).…”

Section: As Indicated Inmentioning

confidence: 99%

Prothrombin is a binding partner of the human receptor of advanced glycation end products

Degani

Altomare

Digiovanni

et al. 2020

Journal of Biological Chemistry

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The receptor for advanced glycation end products (RAGE) plays a key role in mammal physiology and in the etiology and progression of inflammatory and oxidative stress-based diseases. In adults, RAGE expression is normally high only in the lung where the protein concentrates in the basal membrane of alveolar Type I epithelial cells. In diseases, RAGE levels increase in the affected tissues and sustain chronic inflammation. RAGE exists as a membrane glycoprotein with an ectodomain, a transmembrane helix and a short carboxyl-terminal tail, or as a soluble ectodomain that acts as a decoy receptor (sRAGE). VC1 domain is responsible for binding to the majority of RAGE ligands including advanced glycation end products (AGEs), S100 proteins and HMGB1. To ascertain whether other ligands exist, we analyzed by MS the material pulled-down by VC1 from human plasma. Twenty out of 295 identified proteins were selected and associated to coagulation and complement processes and to extracellular matrix. Four of them contained a γ-carboxyl glutamic acid (Gla)-domain, a calcium-binding module, and prothrombin (PT) was the most abundant. Using MicroScale Thermophoresis, we quantified the interaction of PT with VC1 and sRAGE in the absence or presence of calcium that acted as a competitor. PT devoid of the Gla-domain (PT des-Gla) did not bind to sRAGE, providing further evidence that the Gla-domain is critical for the interaction. Finally, the presence of VC1 delayed plasma clotting in a dose-dependent manner. We propose that RAGE is involved in modulating blood coagulation presumably in conditions of lung injury

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Advanced lipoxidation end products (ALEs) as RAGE binders: Mass spectrometric and computational studies to explain the reasons why

Cited by 35 publications

References 34 publications

Type III intermediate filaments as targets and effectors of electrophiles and oxidants

Type III intermediate filaments as targets and effectors of electrophiles and oxidants

The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity

Prothrombin is a binding partner of the human receptor of advanced glycation end products

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