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

Abstract

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.

Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats

“…PvCSP peptides have glycine and proline contents of ~22-33% and ~7-11%, respectively, and thus are predicted to fall within the transition region separating amyloidogenic from elastomeric proteins, the latter of which include elastin domains and insect resilin 14 (Rauscher et al, 2006). Moreover, the elastic modulus of PvCSP peptides [~3-5 cal/(mol Å 2 )] is commensurate with the elastic modulus of peptides modeled after human elastin [~9 cal/(mol Å 2 )], which requires extensibility and elasticity for its physiological function (Reichheld et al, 2021). This analogy supports the observation that CSP is inherently elastic and suggests that achieving a high degree of conformational disorder may be an essential aspect of CSP function on the surface of sporozoites.…”

Structural and physical basis for the elasticity of elastin

“…The study of these typical elastin repeats is of particular interest when it comes to understanding tropoelastin through its characteristic elements. For instance, VPG motifs have been suggested to form transient β-turn structures which are necessary to maintain conformational flexibility (Reichheld et al, 2021).…”

“…The coacervation process is a liquid-liquid phase separation resulting in the formation of a dense protein-rich phase, the coacervate (Johnson and . For elastin, the coacervate corresponds to a functional hydrated state and its water content is in the range of 40-60% (Rauscher and Pomès, 2017;Reichheld et al, 2017). The peculiar physical properties of coacervated states limit the use of structural characterisation methods because they exhibit an intrinsic disorder (Reichheld et al, 2017).…”

“…A computational study of self-assembled ELPs led to a detailed description of a liquid-like, disordered protein state, which may be called the liquid state of proteins and represents the first atomistic model of a protein coacervate (Rauscher and Pomès, 2017). Importantly, the detailed comparison of the equilibrium structure of hydrophobic domains successively in dilute and phase-separated states provides insight into the molecular basis of elasticity.…”

“…This phenomenon is remarkably important when the elastin coacervate is considered as elastin chains are extremely dynamics. Nevertheless, results obtained on the molecular basis for phase separation of hydrophobic elastin-like domains, block copolymer peptides mimicking alternating hydrophobic and cross-linking domains, or mini-elastin provide important insights into the structural and physicochemical basis for the elasticity of elastin (Rauscher and Pomès, 2017;Reichheld et al, 2017;Vidal Ceballos et al, 2022).…”