Elastin architecture

doi:10.1016/j.matbio.2019.07.005

Matrix Biology

Volume 84, November 2019, Pages 4-16

https://doi.org/10.1016/j.matbio.2019.07.005 Get rights and content

Highlights

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Elastin is required for elasticity in diverse vertebrate tissues.
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In mammals, elastin forms a very persistent, elastic crosslinked protein network that is not normally synthesized beyond the first few years of life.
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Tropoelastin is encoded by one gene in most vertebrates and subject to variable splicing
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Tropoelastin is crosslinked to form elastin
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Tropoelastin is a soluble asymmetric protein monomer with a defined set of structures that interconvert between an ensemble of defined, low energy states.
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Tropoelastin displays distinctive association by coacervation.

Abstract

Elastic fibers are an essential component of the extracellular matrix where they provide structural integrity and elastic recoil in a number of important tissues. A major constituent of these fibers is elastin, an insoluble metabolically stable polymer formed via extensive crosslinking of the monomeric precursor tropoelastin. Research over the past few decades has shown that tropoelastin possesses unique structural features that differ from both intrinsically disordered and globular proteins. This review details the advances in our understanding of tropoelastin's structural properties and illustrates how these dictate its biological function.

Introduction

Elastic fibers are integral components of the resilient extracellular matrix (ECM) in all vertebrates. They provide the structural support and elastic recoil required for the continuous mechanical stretching and recovery of soft force-bearing tissues with durability and persistence. The major component of these fibers is elastin, an insoluble polymer that is very persistent, due to extensive crosslinking and is normally a metabolically stable unit over the human lifespan [1].

Tropoelastin is the soluble monomer precursor of elastin that is secreted as a 60 kDa mature protein through variable splicing by diverse elastogenic cell types including fibroblasts, endothelial, smooth muscle, and airway epithelial cells in addition to chondrocytes and keratinocytes [[2], [3], [4], [5], [6], [7]]. Mutations in the tropoelastin gene contribute to the genetic diseases supravalvar aortic stenosis and occasionally cutis laxa [8]. Tropoelastin is characterized by lysine-rich crosslinking domains, which are interspersed with hydrophobic domains that consist primarily of non-polar aliphatic amino acids [9] that often comprise repeating motifs [[10], [11], [12], [13]]. Following translation, tropoelastin is chaperoned to the cell surface by a partly characterized pathway that includes the elastin binding protein (EBP), after which the tropoelastin is secreted [[14], [15], [16], [17]]. Tropoelastin self-aggregates on the cell surface before being deposited onto fibrillin microfibrils and crosslinked to form elastic fibers, in a complex multi-step process collectively referred to as elastogenesis [[18], [19], [20], [21], [22]].

Tropoelastin possesses a structure that is organized enough for assembly but flexible enough to confer elasticity, which has made investigations into aspects of its structure challenging. On this basis it is incorrect to refer to tropoelastin as a disordered structure. Knowledge of tropoelastin's structure has progressed through gene studies, analysis of its encoded domains, and culminated in the realization that structural appreciation can be drawn from holistically examining the structural features of the full-length molecule.

Section snippets

Tropoelastin gene, expression and alternative splicing

A single gene encodes tropoelastin in nearly all species, while teleosts and amphibians are exceptions with two functional genes [[23], [24], [25]]. In humans, tropoelastin is localized to chromosome 7q11.1 and typically expresses 34 out of 36 exons, plus an occasionally used exon 26A in humans [23,[26], [27], [28]]. The hydrophilic crosslinking domains and hydrophobic domains are encoded by distinct alternating exons that preserve the reading frame and allow for alternative splicing in a

Structure elements in tropoelastin

Tropoelastin possesses a unique structure possessing a mosaic of domains in various states of order. Unlike structured proteins which can have a funnel-shaped energy minimum representing the native folded structure (Fig. 1A) [40], the free energy landscape of tropoelastin encompasses multiple energy minima with no sizable barriers between them (Fig. 1B). The molecule transitions easily between these low energy minima, giving rise to a conformational ensemble that comprises a wide array of

Early research into tropoelastin structure

Early research into the structure of tropoelastin was hampered by the insolubility of highly crosslinked elastic fibers, the lack of information afforded by primary sequence analysis due to enrichment for few amino acids (glycine, proline, leucine, alanine and valine), its alternative splicing and its relatively large size (~60–72 kDa) [49,50]. As a result, researchers focused on simpler soluble elastin-like products that often either comprised repeated elements of less than 2% of the sequence

Domain structure of tropoelastin

Exon 1 encodes a signal sequence that is cleaved from tropoelastin during transit through the rough endoplasmic reticulum [67,68]. Domains encoded by the remaining exons can be broadly classified based on the observation that the cassette-like organization alternates between crosslinking domains and hydrophobic domains. The secondary structure adopted by these different domain types are generally observed in water, and trifluoroethanol (TFE) which favors intramolecular hydrogen bonding and

Structural and functional regions in tropoelastin

Over recent decades, a large body of research focused on methodologically deconstructing tropoelastin down to its individual domain or groups of domains to provide insight into the defining features of tropoelastin and how these might contribute to its overall structure and biological function. However, these approaches did not shed appreciable light on the intact molecule. A breakthrough came by deciphering the nanostructure of tropoelastin using SAXS and neutron scattering data, which

Coacervation of tropoelastin and its subsequent crosslinking into elastin

The regulation of coacervation and subsequent crosslinking of tropoelastin into elastic fibers is a highly complex process involving several key accessory proteins including fibulin-4, fibulin-5, latent transforming growth factor β binding protein 4 (LTBP-4), and microfibril associated protein 4 (MFAP4) [[117], [118], [119], [120], [121], [122], [123]]. Due to space limitations, consideration focuses here on coacervation and crosslinking of tropoelastin, while comprehensive descriptions of the

Acknowledgements

H.V. acknowledges an Australian Postgraduate Award and Australian Government Research Training Program Stipend Scholarship. A.S.W. acknowledges funding from the Australian Research Council, National Health ;and Medical Research Council and RSL Australia.

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Elastin architecture

Highlights

Abstract

Introduction

Section snippets

Tropoelastin gene, expression and alternative splicing

Structure elements in tropoelastin

Early research into tropoelastin structure

Domain structure of tropoelastin

Structural and functional regions in tropoelastin

Coacervation of tropoelastin and its subsequent crosslinking into elastin

Acknowledgements

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