A comprehensive map of human elastin cross‐linking during elastogenesis

Hedtke, Tobias; Schräder, Christoph U.; Heinz, Andrea; Hoehenwarter, Wolfgang; Brinckmann, Jürgen; Groth, Thomas; Schmelzer, Christian E.H.

doi:10.1111/febs.14929

Cited by 34 publications

(53 citation statements)

References 73 publications

(151 reference statements)

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“…In our recent studies of bovine and human elastin, we sequenced several tetrafunctionally cross‐linked peptides, in which all assignable peptide strands were derived from KA domains. In human elastin, the single‐Lys cross‐linking domain 14 was found to be involved in DES/IDES formation together with two other KA domains, which is in contrast to the previously described assumptions that postulated the involvement of only two KA domains in DES/IDES formation …”

Section: Lysyl Oxidase‐mediated Cross‐linkingcontrasting

confidence: 96%

“…In conclusion, recent studies have shown that distinct Lys residues can be involved in different types of cross‐links or even remain unaltered . One of the many examples for this diversity is Lys‐104 in domain 6 of human elastin (see Figure , left half).…”

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 88%

“…Lya is highly reactive and participates in the subsequent formation of nonenzymatic cross‐links. On average, ~90% of all Lys residues per TE molecule are modified, that is, they are either derivatized to Lya or incorporated into cross‐links . This indicates that the modification is partial, which is fundamental for the subsequent condensation reactions, of which most require the availability of free Lys residues.…”

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 99%

“…Elastases including some serine, cysteine, and metalloproteases serve this purpose, and cross‐linking sites can be identified by analyzing the released cross‐linked peptides. While peptide sequences and cross‐link locations have been determined in the past with classical methods such as Edman degradation, more recent studies utilized sensitive high‐resolution mass spectrometric (MS) analyses in combination with customized software . Bifunctional intradomain cross‐links release internally cross‐linked peptides with a cyclic structure upon hydrolysis, whereas bi‐ and higher functional interdomain cross‐links are released as interconnected peptide species, which are challenging with respect to their analyses.…”

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 99%

“…On the other hand, this stabilization of secondary structural elements is related to a steric compression of the hydrophilic cross‐linking regions, and one could speculate that this might be beneficial for hydrophobic hydration, which is a basic requirement for elastin's elasticity. Studies have shown that bifunctional LNL and AA intradomain cross‐links can be found in every TE cross‐linking domain . So far, intradomain linkages and their influence on elastin's structure and properties have not been investigated, and they are considered as remains of the multistep pathway of higher functional cross‐linking.…”

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 99%

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Unique molecular networks: Formation and role of elastin cross‐links

2019

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Elastic fibers are essential assemblies of vertebrates and confer elasticity and resilience to various organs including blood vessels, lungs, skin, and ligaments. Mature fibers, which comprise a dense and insoluble elastin core and a microfibrillar mantle, are extremely resistant toward intrinsic and extrinsic influences and maintain elastic function over the human lifespan in healthy conditions. The oxidative deamination of peptidyl lysine to peptidyl allysine in elastin's precursor tropoelastin is a crucial posttranslational step in their formation. The modification is catalyzed by members of the family of lysyl oxidases and the starting point for subsequent manifold condensation reactions that eventually lead to the highly cross‐linked elastomer. This review summarizes the current understanding of the formation of cross‐links within and between the monomer molecules, the molecular sites, and cross‐link types involved and the pathological consequences of abnormalities in the cross‐linking process.

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Section: Lysyl Oxidase‐mediated Cross‐linkingcontrasting

confidence: 96%

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 88%

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 99%

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 99%

Section: Lysyl Oxidase‐mediated Cross‐linkingmentioning

confidence: 99%

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Unique molecular networks: Formation and role of elastin cross‐links

2019

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Genetics of Cutis Laxa

Beyens

Callewaert

2023

Encyclopedia of Life Sciences

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Cutis laxa syndromes are a heterogeneous group of multisystem disorders with prominent connective tissue features including loose redundant skin folds, a clinical hallmark shared among all subtypes. The skin laxity results from severe dermal elastic fibre fragmentation. The molecular defects underlying congenital forms of cutis laxa may affect any step in elastic fibre assembly, as illustrated by the identification of pathogenic variants in different extracellular matrix proteins, including elastin, latent transforming growth factor β proteins and fibulins ( ELN , LTBP4 , FBLN4 , FBLN5, LOX, EMILIN1, LTPB1 ), cellular trafficking ( ATP6V0A2, ATP6V1E1, ATP6V1A and ATP7A ) and metabolic processes ( ALDH18A1, PYCR1) . The latter two groups have been referred to as neurometabolic cutis laxa and may present with skeletal and neurological phenotypes in addition to connective tissue manifestations. Key Concepts Elastic fibres (EF) provide resilience and elasticity to the connective tissue and contribute to tissue homeostasis by regulating cytokine signalling and cell–matrix interactions. Elastic fibre synthesis or elastogenesis is a complex spatiotemporally regulated multistep process. Cutis laxa syndromes are a heterogeneous group of multisystem connective tissue disorders that share loose redundant skin folds, that vary significantly in severity and spectrum of the associated clinical manifestations. The molecular defects underlying congenital forms of cutis laxa involve all steps in EF synthesis, affecting different extracellular matrix proteins ( ELN, LTBP4, FBLN4, FBLN5, LOX, EMILIN1, LTBP1 ), cellular trafficking ( ATP6V0A2, ATP6V1E1, ATP6V1A, SCYL1BP1 and ATP7A ) and metabolism ( ALDH18A1, PYCR1 ). Cutis laxa caused by defects in extracellular matrix proteins present with prominent arterial and/or pulmonary abnormalities. Cutis laxa caused by intracellular trafficking disorders and/or metabolic disorders may present with intellectual deficiency, skeletal and/or ocular defects.

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The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin

Reichheld¹,

Muiznieks

Huynh³

et al. 2020

Biopolymers

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Elastin is a major polymeric protein of the extracellular matrix, providing critical properties of extensibility and elastic recoil. The rs2071307 genomic polymorphism, resulting in the substitution of a serine for a glycine residue in a VPG motif in tropoelastin, has an unusually high minor allele frequency in humans. A consequence of such allelic heterozygosity would be the presence of a heterogeneous elastin polymer in up to 50% of the population, a situation which appears to be unique to Homo sapiens. VPG motifs are extremely common in hydrophobic domains of tropoelastins and are the sites of transient β‐turns that are essential for maintaining the conformational flexibility required for its function as an entropic elastomer. Earlier data demonstrated that single amino acid substitutions in tropoelastin can have functional consequences for polymeric elastin, particularly when present in mixed polymers. Here, using NMR and molecular dynamics approaches, we show the rs2071307 polymorphism reduces local propensity for β‐turn formation, with a consequent increase in polypeptide hydration and an expansion of the conformational ensemble manifested as an increased hydrodynamic radius, radius of gyration and asphericity. Furthermore, this substitution affects functional properties of polymeric elastin, particularly in heterogeneous polymers mimicking allelic heterozygosity. We discuss whether such effects, together with the unusually high minor allele frequency of the polymorphism, could imply some some evolutionary advantage for the heterozygous state.

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A comprehensive map of human elastin cross‐linking during elastogenesis

Cited by 34 publications

References 73 publications

Unique molecular networks: Formation and role of elastin cross‐links

Unique molecular networks: Formation and role of elastin cross‐links

Genetics of Cutis Laxa

The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin

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