Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly

Abstract

Tropoelastin’s local and global structures dictate molecular dynamics and are essential for efficient assembly into elastin.

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

“…[13] In general, hydrophobic domains are responsible for phase separation, self-assembly, and elastomeric properties, while crosslinking domains contain the lysine residues destined for covalent cross-linking. [14,[16][17][18][19][20][21][22] Although there is a single gene for human tropoelastin (hTE), several splice variants [23][24][25] and at least 13 RefSeq isoforms have been identified for the protein. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Such recombinant forms of tropoelastin have been used extensively in vitro to demonstrate that relatively modest changes in sequence and domain arrangements can have significant effects on assembly and material properties.…”

Perspectives on the Molecular and Biological Implications of Tropoelastin in Human Tissue Elasticity

“…Despite the intrinsic flexibility of tropoelastin as a supposedly disordered elastomeric protein, [21] local changes to its native shape, manifested by a perturbed hinge region in human tropoelastin, can have a substantial impact on function, including its assembly into larger-scale structures. [13] This presents a structural paradox: tropoelastin is flexible, yet it maintains a defined solution shape to fulfil its competing structural requirements for both elasticity and assembly. These dual competing requirements are unusual for studied proteins, so we have begun the process of identifying new principles for this class of elastic protein, by reconciling the dual requirements for structural flexibility for elasticity and structural order for regional cooperative demands to facilitate efficient protein self-assembly into elastic fibres.…”

“…Elastin is decorated (,10 % w/w) by microfibrillar proteins. We discovered that tropoelastin has a defined monomer shape in solution that is needed for assembly, [9,10,13] but also displays a large percentage of flexible, disordered regions needed for molecular elasticity. [14,15] The tertiary structure of human tropoelastin represents an ensemble of elastic conformers, [10,16] yet occasional conserved sequence elements hint at requirements for functional demands in one or more key parts of this molecule.…”

“…This model of tropoelastin dynamics describes a characteristic scissors-like motion between the hinge and foot regions, as well as a twisting motion in the N-terminal coil region, in which the N-terminus experiences highest displacement. [9,10,13,20] The geometric distribution of the tropoelastin molecular volume intrinsically prompts a cohesive motion pattern between the upper and lower regions of the molecule, giving rise to local regions of conformational flexibility thought to be responsible for elastic deformation, while maintaining a defined tertiary shape with distinct functional segments for protein and cellular interactions. Despite the intrinsic flexibility of tropoelastin as a supposedly disordered elastomeric protein, [21] local changes to its native shape, manifested by a perturbed hinge region in human tropoelastin, can have a substantial impact on function, including its assembly into larger-scale structures.…”

“…These dual competing requirements are unusual for studied proteins, so we have begun the process of identifying new principles for this class of elastic protein, by reconciling the dual requirements for structural flexibility for elasticity and structural order for regional cooperative demands to facilitate efficient protein self-assembly into elastic fibres. [13] Elastic tissue assembly is poorly understood, yet provides the opportunity to elucidate the key molecular interactions and temporal sequence, because tropoelastin is predominantly a self-assembling system. To emphasize the extraordinary versatility of this protein monomer, tropoelastin is encoded by a single gene but is found in multiple structures and locations in all vertebrates except the cyclostomes.…”