Single nucleotide polymorphisms and domain/splice variants modulate assembly and elastomeric properties of human elastin. Implications for tissue specificity and durability of elastic tissue

Abstract

Polymeric elastin provides the physiologically essential properties of extensibility and elastic recoil to large arteries, heart valves, lungs, skin and other tissues. Although the detailed relationship between sequence, structure and mechanical properties of elastin remains a matter of investigation, data from both the full-length monomer, tropoelastin, and smaller elastin-like polypeptides have demonstrated that variations in protein sequence can affect both polymeric assembly and tensile mechanical properties. Here we model known splice variants of human tropoelastin (hTE), assessing effects on shape, polymeric assembly and mechanical properties. Additionally we investigate effects of known single nucleotide polymorphisms in hTE, some of which have been associated with later-onset loss of structural integrity of elastic tissues and others predicted to affect material properties of elastin matrices on the basis of their location in evolutionarily conserved sites in amniote tropoelastins. Results of these studies show that such sequence variations can significantly alter both the assembly of tropoelastin monomers into a polymeric network and the tensile mechanical properties of that network. Such variations could provide a temporal- or tissue-specific means to customize material properties of elastic tissues to different functional requirements. Conversely, aberrant splicing inappropriate for a tissue or developmental stage or polymorphisms affecting polymeric assembly could compromise the functionality and durability of elastic tissues. To our knowledge, this is the first example of a study that assesses the consequences of known polymorphisms and domain/splice variants in tropoelastin on assembly and detailed elastomeric properties of polymeric elastin.

Direct observation of structure and dynamics during phase separation of an elastomeric protein

“…1C). The stress relaxation of ELP 3 was greater than that of tropoelastin, but remains in the normal range for elastins and ELPs (41,42). Taken together, these data demonstrate that ELP 3 recapitulates the fundamental macroscopic properties of the monomeric, coacervated, and cross-linked forms of tropoelastin.…”

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

“…21 Elastin dysfunction is associated with incompletely penetrant supravalvular aortic stenosis and other vascular lesions, none of which were found on examination using cardiac computed tomography. In the same participant, we detected a likely pathogenic frameshift variant in LZTR1, associated with increased risk for schwannomas.…”

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

“…It has been shown that the insertion or deletion of TE domains or the mutation of certain amino acid residues affects diverse mechanisms associated with the assembly of TE monomers into a polymeric network such as coacervation and cross‐linking processes as well as the resultant mechanical properties. This suggests that variations in the TE sequence allow tissue‐specific alterations in elastin properties or are responsible for abnormal fiber formation under pathological conditions …”

“…This suggests that variations in the TE sequence allow tissue-specific alterations in elastin properties or are responsible for abnormal fiber formation under pathological conditions. [15][16][17] TE's sequence is highly repetitive and about 80% are composed of the four amino acids Gly, Ala, Val, and Pro. The precursor has alternating hydrophobic and more hydrophilic domains, which are encoded by individual exons, so that the domain structure of the protein is reflected in the exon organization of its gene.…”