Elastin is heterogeneously cross-linked

Schräder, Christoph U.; Heinz, Andrea; Majovsky, Petra; Mayack, Berin Karaman; Brinckmann, Jürgen; Sippl, Wolfgang; Schmelzer, Christian E.H.

doi:10.1074/jbc.ra118.004322

Cited by 57 publications

(62 citation statements)

References 64 publications

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“…Kagan et al reported the highest LOX activity for the synthetic polypeptide (AK) n . Our results, however, are in line with recently published data, especially with respect to specific Lys residues which are simultaneously involved in different molecular interconnections in bovine elastin [24]. However, the majority of the peptides derived from KA domains with Lys-Phe, Tyr-Lys or Lys-Tyr motifs was cross-linked via LNL.…”

Section: Discussionsupporting

confidence: 92%

“…While various previous studies focused on particular events of elastogenesis predominantly using immunohistochemical techniques [4,11,[29][30][31][32][33], elastin's molecular structure remains unknown. This workflow, which we applied also in this study, is based on the purification of elastin, its enzymatic hydrolysis and the subsequent analysis of the released peptides using an untargeted mass spectrometry-based sequencing approach [24]. We have recently introduced an approach to overcome these analytical challenges and to gain deeper insight into elastin's structure.…”

Section: Discussionmentioning

confidence: 99%

“…Hydrophilic, that is, putative cross-linked peptides for the analysis of tetrafunctional cross-links from aortic elastin were enriched as described previously [24]. The digestion of aortic elastin was performed with PE ( EC 3.4.21.36) at an enzyme-to-substrate ratio of 1 : 50 (w/w) at 37°C and stopped after 24 h by adding 0.5% (v/v) TFA.…”

Section: In-solution Digestion Of Elastinmentioning

confidence: 99%

“…A modified sequence of human tropoelastin IF 2 was used to identify intramolecular cross-linked peptides with PEAKS as described recently [24]. Furthermore, the processed spectra of all samples were exported as MGF files and analyzed both by using the STAVROX software (version 3.5.1) [70] and by manual validation to identify intra-and interpeptidal cross-links.…”

Section: Identification Of Bifunctional Intra-and Interpeptidal Crossmentioning

confidence: 99%

“…The reaction of one Lya residue with another Lys residue via Schiff base reaction results in the formation of the bifunctional imine cross-link dehydrolysinonorleucine (DLNL) which can be further reduced to the secondary amine cross-link lysinonorleucine (LNL) [14,15]. We discovered many intramolecular cross-links in an overall randomized cross-linking network in bovine aortic elastin [24]. DLNL and AA then further condense with each other, partly with participation of unmodified Lys residues or with other intermediates, to form different trifunctional cross-links as well as the tetrafunctional pyridinium cross-links desmosine (DES) and its structural isomer isodesmosine (IDES), that are unique to elastin [3,17,18].…”

Section: Introductionmentioning

confidence: 99%

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A comprehensive map of human elastin cross‐linking during elastogenesis

et al. 2019

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Elastin is an essential structural protein in the extracellular matrix of vertebrates. It is the core component of elastic fibers, which enable connective tissues such as those of the skin, lungs or blood vessels to stretch and recoil. This function is provided by elastin's exceptional properties, which mainly derive from a unique covalent cross‐linking between hydrophilic lysine‐rich motifs of units of the monomeric precursor tropoelastin. To date, elastin's cross‐linking is poorly investigated. Here, we purified elastin from human tissue and cleaved it into soluble peptides using proteases with different specificities. We then analyzed elastin's molecular structure by identifying unmodified residues, post‐translational modifications and cross‐linked peptides by high‐resolution mass spectrometry and amino acid analysis. The data revealed the presence of multiple isoforms in parallel and a complex and heterogeneous molecular interconnection. We discovered that the same lysine residues in different monomers were simultaneously involved in various cross‐link types or remained unmodified. Furthermore, both types of cross‐linking domains, Lys‐Pro and Lys‐Ala domains, participate not only in bifunctional inter‐ but also in intra‐domain cross‐links. We elucidated the sequences of several desmosine‐containing peptides and the contribution of distinct domains such as 6, 14 and 25. In contrast to earlier assumptions proposing that desmosine cross‐links are formed solely between two domains, we elucidated the structure of a peptide that proves a desmosine formation with participation of three Lys‐Ala domains. In summary, these results provide new and detailed insights into the cross‐linking process, which takes place within and between human tropoelastin units in a stochastic manner.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: In-solution Digestion Of Elastinmentioning

confidence: 99%

Section: Identification Of Bifunctional Intra-and Interpeptidal Crossmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A comprehensive map of human elastin cross‐linking during elastogenesis

et al. 2019

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Acquired Disorders of Dermal Connective Tissue

Fahy,

Lovell

2024

Rook's Textbook of Dermatology

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This chapter reviews acquired changes in dermal connective tissue during normal ageing and in disease processes, including photodamage. Corticosteroids are a potent cause of dermal atrophy, which may also be congenital or induced by inflammatory disorders related to morphoea. Enzymatic degradation of elastic tissue results in localised or generalised skin laxity, which resembles genetic disorders such as pseudoxanthoma elasticum and cutis laxa. In contrast, some disorders are characterised by excessive deposition of collagen or elastic tissue. Fibrosis is associated with contracture, which causes deformity and restricted movement as in palmoplantar fibromatosis. Several chemical environmental triggers induce diffuse fibrosis resembling systemic sclerosis. Keloids represent an abnormal scarring response to trauma. Finally, dermal connective tissue components may be extruded via the epidermis in perforating disorders such as elastosis perforans serpiginosa.

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Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging

et al. 2023

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The understanding of the contribution of the tumour microenvironment to cancer progression and metastasis, in particular the interplay between tumour cells, fibroblasts and the extracellular matrix has grown tremendously over the last years. Lysyl oxidases are increasingly recognised as key players in this context, in addition to their function as drivers of fibrotic diseases. These insights have considerably stimulated drug discovery efforts towards lysyl oxidases as targets over the last decade. This review article summarises the biochemical and structural properties of theses enzymes. Their involvement in tumour progression and metastasis is highlighted from a biochemical point of view, taking into consideration both the extracellular and intracellular action of lysyl oxidases. More recently reported inhibitor compounds are discussed with an emphasis on their discovery, structure‐activity relationships and the results of their biological characterisation. Molecular probes developed for imaging of lysyl oxidase activity are reviewed from the perspective of their detection principles, performance and biomedical applications.

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Elastin is heterogeneously cross-linked

Cited by 57 publications

References 64 publications

A comprehensive map of human elastin cross‐linking during elastogenesis

A comprehensive map of human elastin cross‐linking during elastogenesis

Acquired Disorders of Dermal Connective Tissue

Lysyl Oxidases as Targets for Cancer Therapy and Diagnostic Imaging

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