Extracellular matrix: from atomic resolution to ultrastructure

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The extracellular matrix (ECM) is a highly organized multimolecular structure, essential for life in higher organisms. Although substantial high-resolution structural information is available for relatively small fragments of ECM components, the inherent difficulty in preparing and analyzing samples of large, fibrous polymers impedes structural efforts. Here, we review recent advances in understanding the structure of three important ECM components: collagen, fibrillin and fibronectin. Emphasis is placed on the key role of intermolecular interactions in assembling larger, μm scale, structures.

Introduction

The extracellular matrix (ECM) is a complex network of glycoproteins and proteoglycans that originated with the advent of multicellular organisms [1]. Cells generate well-ordered ECM-complexes to surround and support themselves. The ECM then plays an essential role in the survival, migration and proliferation of these adjoining cells. Continuous ECM remodeling, catalyzed by various degradation enzymes, is common, and the arrangement and concentration of different macromolecules gives rise to a wide diversity of ECM forms in the various tissue types (skin, bone, cornea of the eye, etc.) [2]. The structure of the constituent polymers is rather well known at the domain or fragment level but is less well known at the levels of intact molecule or higher. The monomeric subunits are large, multi-domain and often inherently flexible, thus presenting problems to atomic resolution techniques such as single crystal diffraction or NMR. The polymers formed retain substantial heterogeneity and are cross-linked and difficult to extract from the matrix in undamaged form. Although progress is relatively slow, new approaches and tools are beginning to have an impact.

In this brief review, we have chosen to illustrate this field by discussing recent structural studies and current understanding of three archetypal ECM proteins: collagen (the most abundant protein in mammals), fibrillin and fibronectin. The first is a biopolymer of characteristic amino acid sequence, while the last two are modular proteins, constructed from repeating, autonomously folding domains with a high degree of structural similarity [3]. A major remaining structural problem is to define the various inter and intramolecular interactions made by molecules, especially in the context of structure at the μm level. We appreciate that this selection, with only three proteins, neglects many other important ECM molecules and provides only a part of the picture, however, space is limited. A particular area of neglect is polysaccharides, such as hyaluronan [4] which, with its receptors [5], plays a pivotal role in ECM hydration and elasticity.

Section snippets

Collagen

Collagen has a characteristic three residue repeat, Gly-Xaa-Yaa, in its primary structure, which results in a stable triple-helical conformation with the glycine residues at the core of the helix [6, 7, 8]. Proline and 4-hydroxyproline residues, usually found in positions Xaa and Yaa, function to stabilize the three individual polyproline II-like helices. After post-translational modification, secreted collagen helices self-assemble to cross-linked microfibrils and eventually μm-long fibrils.

Fibrillin

Fibrillin-1 is a large (350 kDa) multidomain glycoprotein that forms the major structural component of 10–12 nm elastic microfibrils in the ECM [22, 23]. With elastin, it provides the necessary elasticity and resilience of a variety of tissues. A large number of matrix components that interact with fibrillin-1 have been identified, including integrins [24], heparin [25], latent transforming growth factor β-binding proteins and fibulin-2 [26]. These, together with homotypic fibrillin

Fibronectin

Fibronectin (FN) is a large dimeric plasma glycoprotein found only in vertebrates. FN is composed of three different domain types, FNI, FNII and FNIII, high-resolution structures of which have been available for some time [35]. A tightly controlled process transforms plasma FN to a fibrillar form within the ECM. Little is known about the fibrillogenesis process, or the structure of the fibrillar matrix formed. It is, however, believed that FN interdomain interactions [36, 37, 38, 39, 40, 41, 42•

Conclusion

In all three ECM molecules visited, association interactions are the key to understand higher order structures. Intermolecular interactions define the packing order of collagen [18••], inter-domain interactions have a major role in models of fibrillin [27] (whether ‘pleated’ or staggered) and interdomain association sites lead directly to FN fibrillogenesis models [50••]. Detailed structural descriptions of module interactions are, comparatively, fewer than structures of individual modules [3

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgement

Financial support was provided by the Wellcome Trust.

References (51)

  • C.L. Kuo et al.

    Effects of fibrillin-1 degradation on microfibril ultrastructure

    J Biol Chem

    (2007)
  • J.R. Potts et al.

    Structure and function of fibronectin modules

    Matrix Biol

    (1996)
  • K.M. Aguirre et al.

    Fibronectin self-association is mediated by complementary sites within the amino-terminal one-third of the molecule

    J Biol Chem

    (1994)
  • D.C. Hocking et al.

    Fibronectin's III-1 module contains a conformation-dependent binding site for the amino-terminal region of fibronectin

    J Biol Chem

    (1994)
  • S.V. Litvinovich et al.

    Interactions between type III domains in the 110 kDa cell-binding fragment of fibronectin

    J Mol Biol

    (1995)
  • J.L. Sechler et al.

    A novel fibronectin binding site required for fibronectin fibril growth during matrix assembly

    J Cell Biol

    (2001)
  • H.P. Erickson

    Stretching fibronectin

    J Muscle Res Cell Motil

    (2002)
  • T. Ohashi et al.

    Domain unfolding plays a role in superfibronectin formation

    J Biol Chem

    (2005)
  • T. Ohashi et al.

    Dual labeling of the fibronectin matrix and actin cytoskeleton with green fluorescent protein variants

    J Cell Sci

    (2002)
  • I. Vakonakis et al.

    Interdomain association in fibronectin: insight into cryptic sites and fibrillogenesis

    EMBO J

    (2007)
  • B. Alberts et al.

    Molecular Biology of the Cell

    (2002)
  • Z. Werb et al.

    Extracellular matrix remodeling during morphogenesis

    Ann N Y Acad Sci

    (1998)
  • T.C. Laurent et al.

    The structure and function of hyaluronan: An overview

    Immunol Cell Biol

    (1996)
  • S. Banerji et al.

    Structures of the Cd44-hyaluronan complex provide insight into a fundamental carbohydrate–protein interaction

    Nat Struct Mol Biol

    (2007)
  • K.H. Mayo

    NMR and X-ray studies of collagen model peptides

    Biopolymers

    (1996)
  • Cited by (0)

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