Functions of Prolyl Hydroxylation in Elastin

Connective tissues and organs of high tensile strength, like lung, heart and skin, extensively express elastin. Elastin is a key extracellular matrix protein responsible for elasticity, resilience, and mechanical strength in these tissues; on this basis, elastin-based materials have been widely applied in various fields such as tissue regeneration and drug delivery. During elastogenesis, the hierarchical elastic fiber assembly process, elastin is subject to a less-studied post-translational modification, prolyl hydroxylation, where, mediated by prolyl-4-hydroxylase, a hydroxyl group replaces one of the hydrogen atoms at the C-gamma position in proline residues. The structural stability of other connective tissue proteins, such as collagen, is thought to be mediated in part through hydroxylation of proline residues. This calls into question the role of prolyl hydroxylation in elastin. According to recent experimental studies, elastin-like peptides with hydroxyproline modifications are more resistant to enzymatic digestion, and subject to an abnormal behavior in elastogenesis. We hypothesize that hydroxylation alters elastin’s biological behavior via protein-solvent interactions. To substantiate our hypothesis, we used existing mass spectrometry data of elastin samples obtained from humans to build representative molecular models and perform extensive molecular dynamics simulations. As a starting point, we employ our recently developed fully atomistic model of elastin’s precursor, tropoelastin. Our findings suggest that in comparison to prolines, hydroxyprolines exhibit an increase in hydrogen bonding with water and a rise in surrounding hydrophilic hydration. Such enhanced protein-solvent interactions rearrange the residue’s local configurations, reducing elastin’s global dynamics required for essential biological process, thereby preventing it from targeted degradation and hierarchical assembly. Overall, our investigation provides insights into functions of prolyl hydroxylation in elastin at a nanoscopic scale. We propose that strategically-placed hydroxyproline residues may be useful for tuning the sustainability of engineered elastin-based materials.