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Extracellular Matrix Assembly: a Multiscale Deconstruction

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Extracellular Matrix Assembly: a Multiscale Deconstruction FOCUS ON THE EXTRAcELLuLAR MATRIX REVIEWS Extracellular matrix assembly: a multiscale deconstruction Janna K. Mouw1, Guanqing Ou1,2 and Valerie M. Weaver1,3–6 Abstract | The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue. The extracellular matrix (ECM) has important roles in can function both as support for cells and as active regulating the development, function and homeostasis of participants in signalling to control cell behaviour9,10. all eukaryotic cells1–3. In addition to providing physical In all cases, each class of ECM molecule has evolved the support for cells, the ECM actively participates in the ability to interact with another class to produce unique establishment, separation and maintenance of differen- physical and signalling properties that support tissue tiated tissues and organs by regulating the abundance structure, growth and function1. Growing insight into 1Center for Bioengineering of growth factors and receptors, the level of hydration the biological importance of the ECM in development, 1,4 and Tissue Regeneration, and the pH of the local environment . These diverse patho­physiology and the normal function of tissues Department of Surgery, functions are achieved through its complex chemical throughout the body has confirmed the importance of University of California, composition and organization. Although it is primaril­y elucidating the mechanisms of ECM assembly. San Francisco. 2University of California composed of water, proteins and polysaccharides, This Review provides a general overview of our cur- San Francisco and the ECM shows exquisite tissue specificity as a result rent understanding of the ‘structural principles’ that University of California of the unique ECM compositions and topographies that underlie the assembly of the ECM at several level­s, high- Berkeley Joint Graduate are generated through a dynamic biochemical and bio- lighting key molecular components and their organiza- Group in Bioengineering, physical interplay between the various cells in each tissue tion into an interlocking network. We also consider San Francisco, California 4 94143, USA. and the evolving microenvironment . The mature ECM the biochemical and mechanical cues that affect ECM 3Department of Anatomy, can also undergo dynamic remodelling in response to assembly and how its organization directly relates to University of California, environmental stimuli, such as applied force or injury, its tissue-specific functions, including as a structural San Francisco. which enables the tissue to maintain homeostasis and support, as a barrier between different tissues and as a 4Department of Bioengineering and to respond to physiological challenges and stresses, source of both chemical and physical cues. We highlight 2,5–8 Therapeutic Sciences, includin­g disease . unanswered questions that require further investigation University of California, Understanding cellular differentiation, tissue and the techniques and model systems that may facilitate San Francisco. morphogenesi­s and physiological remodelling requires this research. 5 Eli and Edythe Broad Center an understanding of the ECM components that are of Regeneration Medicine and Stem Cell Research, produced by cells, as well as the assembly of those Key molecular players in the ECM University of California, macromolecules into a functional three-dimensional Our understanding of the composition, structure and San Francisco. structure2,3. The macromolecules that constitute the function of the ECM is continuously evolving, aided by 6UCSF Helen Diller ECM have evolved structural and chemical properties the discovery of novel ECM molecules, the mapping Comprehensive Cancer Center, University of that are particularly suited to their specific biological of internal sites within ECM proteins that are crucial California, San Francisco, functions in their respective tissues. Small, modular for self-assembly and for interactions with other ECM California 94143, USA. subunits form homopolymers and heteropolymers that components, the characterization of the proteases and Correspondence to V.M.W. become supramolecular assemblies with highly special- the protease inhibitors that are responsible for ECM e‑mail: Valerie.Weaver@ ized organizations1–3. These assemblies contain binding degradation and turnover, and the identification of ucsfmedctr.org doi:10.1038/nrm3902 domains for growth factors and chemokines, establish novel receptors and signalling mechanisms that medi- 1–3 Published online complex adhesion surfaces and form diffusion barriers ate cellular responses to the ECM . The architecture 5 November 2014 between different cellular layers; thus, ECM molecules of the ECM is highly organized as a result of the innate NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 15 | DECEMBER 2014 | 771 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS a Standard collagen molecule properties of its constituent molecules and their inter­ N terminal C terminal actions, as well as the activities of resident cells. The propeptide propeptide interaction­s between cells and the environment that 1 Gly-X-Y repeats are created by the ECM in turn have important roles in directing processes in development, homeostasis and 3 α chains (2 α1,1 α2) pathogenesis. In this Review, we define the ECM as all secreted molecules that are immobilized outside a cell, including growth factors, cytokines and cell adhesion molecules, although we primarily focus on the macro- molecules that are mainly responsible for tissue-type C-terminal propeptide 2 initiates triple helix formation specific extracellula­r architecture. in the rough ER The protein and non-protein constituents of the ECM vary not only in terms of their functional roles but also in terms of their structure. The polypeptide chains of ECM macromolecules often consist of many Procollagen is secreted individual domains, and homologous domains between into the extracellular space 3 Procollagen macromolecules can have sequence and structural dif- ferences that impart different functions. Individual ECM macromolecules rarely exist in isolation but Enzymes cleave propeptides instead often integrate into supramolecular structures to form collagen 4 Collagen containing different molecular species that differ in both their identity and their relative abundance. The ECM is primarily composed of two main classes of macromolecules: fibrous proteins (including collagens and elastin) and glycoproteins (including fibronectin, Topographies b FACIT and related collagens proteoglycans (PGs) and laminin)1. The three-dimensional qualities Gly-X-Y interruption of surfaces or structures, including contours and relief. Fibrillar collagens. Collagens are major proteins of the In the context of the ECM this Non-collagen ECM and are arguably the most dominant. Decade­s of includes features such as peaks Collagen research have uncovered 28 different collagen types, and valleys, changes in and each type is comprised of homotrimers and hetero­ roughness and geometric features. trimers that are formed by three polypeptide chains (known as α-chains) (FIG. 1; TABLE 1). More than 40 Morphogenesis distinct α-chains have been identified in humans as Figure 1 | Collagen structure. a | The standard fibrillar The process of cell movement well as multiple other proteins containing collagen- collagen molecule isNature characterized Reviews by| Molecular amino- and Cell Biology during embryonic development like domains11,12. The structural hallmark of all colla- that controls the size, the carboxy-terminal propeptide sequences, which flank a shape and the patterning of series of Gly‑X‑Y repeats (where X and Y represent any gens is their triple helix — a tight right-handed helix tissues and organs. amino acids but are frequently proline and hydroxyproline) of three α-chains, each of which contains one or more (step 1). These form the central triple helical structure of regions characterized by the repeating amino acid motif Proteoglycans procollagen and collagen. Three α‑chains (the illustration Gly‑X‑Y, where X and Y can be any amino acid13 (FIG. 1). (PGs). Glycoproteins that shows two 1-chains and one 2-chain, which is consist of a core protein to α α Some colla­gen molecules assemble as homotrimers, which one or more representative of type I collagen) are intracellularly whereas others assemble as heterotrimers that are com- glycosaminoglycan chain is assembled into the triple helix following initiation of this prised of two or three distinguishable α-chain types. The attached. process by the C‑terminal domain (step 2). Procollagen is large family of collagens and proteins with collagenous secreted by cells into the extracellular space (step 3) and domains has revealed that the collagen triple helix is a Glycosaminoglycans converted into collagen by the removal of the N- and (GAGs). Long, linear, charged C‑propeptides via metalloproteinase enzymes (step 4). basic motif that can be adopted by proteins that have polysaccharides that comprise b | Fibril-associated collagens with interrupted triple helices
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