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Contents 1 Elastin 1.1 Gene 1.2 Structure 1.3 Function 1.4 Diseases 1.5 References

Elastin

Elastin is a fibrous protein that can be found in human connective tissue and gives the tissue its elastic quality. This allows tissues that have been stretched to regain their original shape. Elastin is typically found in tissue such as skin, blood vessels, lungs, and urinary. At the cellular level elastin is found in the extracellular matix. Mature elastin is an insoluble polymer constituted by several tropoelastin molecules covalently bound to each other by cross-links. These can be bi- (lysinonorleucine), tri- (merodesmosine) or tetra-functional (desmosine and isodesmosine) in nature, and the increase in complexity is thought to progress as the fiber matures and ages. Despite its very hydrophobic nature, elastin is highly hydrated by water that swells the polymer in vivo. Mature elastin is extremely stable, and its turnover is so slow it can be assumed that elastin lasts for the entire lifespan of the organism.

Gene

The elastin gene is a single copy gene localized in chromosome 7 in humans and, under normal conditions, is expressed by various cell types during the pre- and neonatal stages of development. The elastin gene product, tropoelastin, is a protein of 750 to 800 residues. As a norm, the elastin gene possesses 36 exons, some of which code for hydrophobic sequences and others for lysine-containing segments.^[1] The introns of the human gene are much larger than the exons and the exon–intron boundaries always split codons in the same manner. This unique feature allows extensive alternative splicing of the primary transcripts without disrupting the reading frame and results in the translation of various tropoelastin isoforms.^[2] Recent results show that this is spatially and developmentally regulated. This relationship is not currently completely understood.^[3]

The tropoelastin then binds to galactolectin, which is a chaperone that prevents premature aggregation of the tropoelastin, and escorts the tropoelastin outside of the cell and into the extracellular matrix. Once here the tropoelastin polypeptides are modified in order for the lysines to be cross-linked between tropoelastin polypeptides which forms the elastin protein.

Structure

Conventionally elastin was thought to be an amorphous polypeptide but recent research and breakthroughs in 2D NMR spectroscopy have lead to some speculation as to some of the possible structures that could be found in elastin. Since the main function of elastin is to provide elasticity to the cell and surrounding tissue it would stand to reason that the protein would need to be very flexible. This would naturally lead to the conclusion that elastin must be glycine rich since this is the most flexible amino acid. Also elastin must have certain biophysical properties in order to provide the function of elasticity. Since elastin provides recoil to tissue elastin must be able to be found in two different states; a relaxed state and a stretched state. 2D NMR spectroscopy currently is unable to show the full structure of elastin, however, certain function groups and amino acids can be assigned to specific peaks of the NMR spectroscopy of elastin. Therefore, this does give a partial picture of the structure of elastin.^[4]

Currently there are two groups working on solving the mystery of elastin's structure and each group has purposed models which share some similarities but also have some differences. The First group is the Birmingham (U.S.A.) group, on the basis of extensive studies on synthetic poly(VPGVG), a repeating sequence of elastin, introduced a structural model supporting a new mechanism of elasticity. With Urry’s model of poly(VPGVG), there is one type II β-turn per pentameric unit with PG at the corner of the bend and a 4→1 hydrogen bond connecting the carboxyl group of the first valine to the amine group of the fourth valine along the sequence. The repetition of this conformational unit gives rise to a helical arrangement called the β-spiral. The β-turns act as spacers between the turns of the spiral.^[5]

In Tamburro’s model, non-recurring, isolated type II β-turns are proposed for (GXGGX) repeating sequences. These have XG or GG segments at the corners with 4→1 hydrogen bonds connecting the first and the fourth glycine or the second and fifth X residue, respectively. Due to the fact that G substitutes for P, the turns are rather labile and, therefore, can interconvert giving rise to dynamical β-turns sliding (Fig. 2) along the chain. Thus, a regular array of β-turns (the Urry β-spiral) cannot be stable enough for these sequences, and the polypeptide chain is freely fluctuating.^[6]

It is important to note that both models describe and apply to different region of elastin. Also, although differing in many ways, both models present a common conformational feature, that is the presence of type II β-turns. However, the dynamic aspects are different and must be viewed differently in regards to the elasticity of the protein. In particular, Tamburro and coworkers have recently studied, through theoretical simulations, the dynamics of GG containing sequences. Using both vacuo and aqueous solution, they attempted to correlate the obtained results with experimental data from classical spectroscopic methods. The experimental approach has been applied to synthetic fragments of the protein comprising di-, tri-, penta-, octa-, deca-, pentadecapeptides, and some of their polycondensation products. The results revealed the presence of two main families of conformers, folded or quasi-folded structures: type I and type II β-turns, γ-turns, half turns; and extended or quasi extended structures: β-sheets, polyproline II conformation. These structures are dynamically interchanging among themselves and also, as in the case of the β-turns, sliding along the chain (Fig. 2), as confirmed by molecular dynamics simulations.^[7]

Function

The only function of elastin, that is currently known, is to provide elasticity to cells and the surrounding tissue. It is able to do this through its very flexible, stretchable, and when required rigid structure. Elastin is found in the extracellular matrix where it interacts with other molecules and other proteins, such as fibrin and collagen.

Diseases

There are many diseases or disorders that can result from a deficiency, absence, malformation, or excess of elastin. While there are many of these such disease or disorders there are three that are more severe and have been studied more. These three diseases and disorders are supravalvular aortic stenosis (SVAS), cutis laxa, and elastoderma.

Supravalvular aortic stenosis (SVAS) is a disease that causes significant narrowing of the large arteries and is inherited either as an isolated, autosomal dominant trait or as part of the Williams syndrome. In both cases, the translated tropoelastin is truncated and thus lacks some cross-link domains as well as the C-terminal region. This could partly explain the observed deposition of abnormal elastic fibers. As the elastic fibers are disorganized, SVAS could possibly result from an adaptation of the “less elastic” vessel to persistent hemodynamic stress, explaining the observed smooth muscle hypertrophy and collagen deposition.^[8] Williams syndrome is a developmental disorder involving the central nervous system and the connective tissues which originates from a deletion of at least 114 kb on one elastin allele. Hemizygosity at the elastin locus can reasonably explain the connective tissue abnormalities contributing to the syndrome (SVAS), but not the neurobehavioral or the other connective tissue features of the Williams syndrome. The most probable hypothesis is that the genetic defect associated with the syndrome involves other unidentified genes whose absence would affect the severity of the connective disorders and could possibly explain the neurobehavioral features of the syndrome.^[9]

Cutis laxa is an elastin related disorder which induces the loss of elastin and elastic fibres in the cutaneous and other connective tissue compartments. Cutis laxa can occur in both genetic and acquired forms and exhibits a considerable variety in its clinical manifestations. For example, in its most severe, perinatal form, the elastic fibres are almost undetectable in the skin and internal organs, leading to the early death of the patient. However, other cutis laxa phenotypes only lead to a mild wrinkling of the skin.The acquired form of cutis laxa is usually a consequence of loss of cutaneous elastic fibres due to local or generalized inflammatory events. This loss is usually due to an increased elastolytic activity, and its severity varies considerably.^[10]

Elastoderma manifests itself with an elastin accumulation in the skin. A large amount of elastic tissue is deposited throughout the dermis replacing the subcutaneous tissue. The protein assembled fibres show considerable polymorphism as compared to normal elastin, and thus the tissue of the organism differs significantly from that of normal elastin containing tissue. “Grape-like” structures can be observed by scanning electron microscopy.^[11] The deficiency lying behind the elastoderma phenotype remains unknown thus far, however, other research has shown that “grape-like” structures very similar to those observed in this disease have been observed when the polypeptide poly(VGVHypG) was left to self-aggregate.^[12] Therefore, it may be possible that elastoderma could be due, at least in part, to extensive post-translational hydroxylation of the prolyl residues of tropoelastin molecules resulting in the chaotic deposition of an elastin-like material.

References

1. ↑ Debelle, L. Elastin: molecular description and function. International of Biochemistry and Cell Biology, 1999, p.261-272DOI: 10.1016/S1357-2725(98)00098-3
2. ↑ Indik Z, Yeh H, Ornstein-Goldstein N, Sheppard P, Anderson N, Rosenbloom JC, Peltonen L, Rosenbloom J. Alternative splicing of human elastin mRNA indicated by sequence analysis of cloned genomic and complementary DNA. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5680-4. PMID:3039501
3. ↑ Debelle, L. Elastin: molecular description and function. International of Biochemistry and Cell Biology, 1999, p.261-272DOI: 10.1016/S1357-2725(98)00098-3
4. ↑ Hong, M. Structure of an elastin-mimetic polypeptide by solid-state NMR chemical shift analysis. Biopolymers, 2003, p.158-168DOI: 10.1002/bip.10431
5. ↑ D. W. Urry, On the molecular structure, function and pathology of elastin: The Gotte stepping stone. in: A. M. Tamburro (Ed.), Elastin and Elastic Tissue, Armento, Potenza, Italy, 1997, pp. 11–22
6. ↑ Debelle, L. Elastin: molecular description and function. International of Biochemistry and Cell Biology, 1999, p.261-272DOI: 10.1016/S1357-2725(98)00098-3
7. ↑ Debelle, L. Elastin: molecular description and function. International of Biochemistry and Cell Biology, 1999, p.261-272DOI: 10.1016/S1357-2725(98)00098-3
8. ↑ Curran, Mark E. The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell, 1993, p.159-168[ http://dx.doi.org.prox.lib.ncsu.edu/10.1016/0092-8674(93)90168-P DOI: 10.1016/0092-8674(93)90168-P]
9. ↑ Ewart, Amanda K. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nature Genetics, 1993, p.11-16DOI:10.1038/ng0993-11
10. ↑ Uitto, J. Molecular pathology of elastin. in: A. M. Tamburro, J. M. Davidson (Eds.), Elastin: Chemical and Biological Aspects. Congedo Editore, Galatina, Italy, 1990, p.303–330
11. ↑ Korneberg, R.L. Elastoderma—Disease of elastin accumulation within the skin. New Engl. J. Med., 1985, pp. 771–775
12. ↑ Sandberg, L.B. Hydroxylation of the pentapeptide VGVPG in ovine elastin. CIBA Found. Symp., 1995, p.51–58