Molecular model of human tropoelastin and implications of associated mutations

Abstract

Protein folding poses unique challenges for large, disordered proteins due to the low resolution of structural data accessible in experiment and on the basis of short time scales and limited sampling attainable in computation. Such molecules are uniquely suited to accelerated-sampling molecular dynamics algorithms due to a flat-energy landscape. We apply these methods to report here the folded structure in water from a fully extended chain of tropoelastin, a 698-amino acid molecular precursor to elastic fibers that confer elasticity and recoil to tissues, finding good agreement with experimental data. We then study a series of artificial and disease-related mutations, yielding molecular mechanisms to explain structural differences and variation in hierarchical assembly observed in experiment. The present model builds a framework for studying assembly and disease and yields critical insight into molecular mechanisms behind these processes. These results suggest that proteins with disordered regions are suitable candidates for characterization by this approach.

Tropoelastin is a Flexible Molecule that Retains its Canonical Shape

“…The tropoelastin monomer represents the dominant building block for elastic fibers (cartoon representation of molecular structure is embedded in a SAXS‐derived outline, based on ref. ). Reproduced with permission .…”

“…The mature form of the secreted human tropoelastin monomer is 60 kDa and is composed of an alternating pattern of repetitive, hydrophobic glycine‐, valine‐, and proline‐rich domains spread out between lysine‐containing cross‐linking domains . Traditionally described as a largely disordered molecule, recent studies suggest that tropoelastin is a flexible molecule with a distinct nanostructure that determines its structural and cell‐adhesive properties.…”

“…A number of computational models have made strides in elucidating the molecular nature of elastin, although the focus of these works has been on shorter elastin‐like peptides or assemblies thereof . For molecules with a high degree of disorder, we and others have shown that enhanced sampling methods such as replica exchange molecular dynamics (REMD) are effective in predicting molecular structure . Following on from our recent work to develop a fully atomistic model of the tropoelastin monomer, here we consider the structural ensemble accessible to the molecule at body temperature, that is, 37 °C.…”

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.…”