Overview of the Matrisome—An Inventory of Extracellular Matrix Constituents and Functions
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Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Overview of the Matrisome—An Inventory of Extracellular Matrix Constituents and Functions Richard O. Hynes and Alexandra Naba Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Correspondence: [email protected] Completion of genome sequences for many organisms allows a reasonably complete definition of the complement of extracellular matrix (ECM) proteins. In mammals this “core matrisome” comprises 300 proteins. In addition there are large numbers of ECM- modifying enzymes, ECM-binding growth factors, and other ECM-associated proteins. These different categories of ECM and ECM-associated proteins cooperate to assemble and remodel extracellular matrices and bind to cells through ECM receptors. Togetherwith recep- tors for ECM-bound growth factors, they provide multiple inputs into cells to control survival, proliferation, differentiation, shape, polarity, and motility of cells. The evolution of ECM pro- teins was key in the transition to multicellularity, the arrangement of cells into tissue layers, and the elaboration of novel structures during vertebrate evolution. This key role of ECM is reflected in the diversity of ECM proteins and the modular domain structures of ECM proteins both allow their multiple interactions and, during evolution, development of novel protein architectures. he term extracellular matrix (ECM) means make up basement membranes. Biochemistry Tsomewhat different things to different of native ECM was, and still is, impeded by people (Hay 1981, 1991; Mecham 2011). Light the fact that the ECM is, by its very nature, and electron microscopy show that extracellular insoluble and is frequently cross-linked. Fur- matrices are widespread in metazoa, underlying thermore, ECM proteins tend to be large, and and surrounding many cells, and comprising early work was frequently on proteolytic frag- distinct morphological arrangements. The ini- ments. The application of molecular biology tial biochemical studies on extracellular matrix to studies of ECM proteins and their genes concentrated on large, structural extracellular uncovered many previously unknown ECM matrices such as cartilage and bone. In the molecules and defined their structures. The 1980s, the availability of model systems such protein chemistry and molecular biology re- as the Engelbreth-Holm-Swarm (EHS) sarcoma vealed that ECM proteins are typically made opened the way to biochemical analyses of up of repeated domains, often encoded in the basement membranes and led to the discovery genome as separate exonic units. The comple- of the different group of ECM proteins that tion of the sequences of many genomes now Editors: Richard O. Hynes and Kenneth M. Yamada Additional Perspectives on Extracellular Matrix Biology available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a004903 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press R.O. Hynes and A. Naba allows description of the entire list of proteins candidate ECM proteins. Negative sweeps of and, potentially, the definition of the complete that list using domains from other protein repertoire of ECM proteins, based on homolo- families (e.g, tyrosine kinases, which share gies with known ECM proteins. Comparative FN3 and Ig domains with ECM proteins) and analyses of the genomes of different organ- screens for transmembrane domains allow isms allow deductions about the evolution of refinement of the list. A very few known this repertoire, which we term the matrisome. ECM proteins do not have readily recognizable Newer methods such as mass spectrometry are domains (e.g., elastin, dermatopontin, and also beginning to allow more detailed biochem- some dentin matrix proteins) although, in- ical characterization of extracellular matrices. In creasingly, even those are now being incorpo- this article, we will give an overview of the mam- rated into protein analysis sites such as malian matrisome and briefly discuss certain SMART and InterPro, allowing their routine aspects of the evolution of the matrisome and capture in the sweeps. Using such methods of the ECM. plus manual annotation, we have been able to define a robust list of the proteins defining the mammalian matrisome by analysis of DEFINITION OF THE MATRISOME the human and mouse genomes (Naba et al. In analyzing the structure and functions of 2011). We call this list of “core” ECM proteins extracellular matrices, one would like to have a the core matrisome. It comprises 1%–1.5% complete “parts list”—a list of all the proteins of the mammalian proteome (without consid- in any given matrix and a larger list of all the ering the contribution of alternatively spliced proteins that can contribute to matrices in isoforms (prevalent in transcripts of mat- different situations (the “matrisome”). As men- risome genes). This list comprises almost 300 tioned, the biochemistry of ECM is challenging proteins, including 43 collagen subunits, three because of the insolubility of most ECMs. How- dozen or so proteoglycans, and around 200 ever, the availability of complete genome se- glycoproteins. quences coupled with our accumulated knowledge This core matrisome list does not include about ECM proteins now makes it possible mucins, secreted C-type lectins, galectins, sem- to come up with a reasonably complete list aphorins, and plexins and certain other groups of ECM proteins. ECM proteins typically con- of proteins that plausibly do associate with the tain repeats of a characteristic set of do- ECM but are not commonly viewed as ECM mains (see figures and Table 1) (LamG, TSPN, proteins; lists of these “ECM-affiliated” proteins FN3, VWA, Ig, EGF, collagen prodomains, are given in Naba et al. (2011). The core matri- etc.). Many of these domains are not unique some list also does not include ECM-modifying to ECM proteins but their arrangements are enzymes, such as proteases, or enzymes highly characteristic. That is, the architecture involved in cross-linking, or growth factors of ECM proteins is diagnostic—they are built and cytokines, although these are well known from assemblies of many ancient, and a few to bind to ECMs (see below). more recent, protein domains, each of which Two useful databases provide information is typically encoded by one or a few exons in on the expression and distribution of various the genome. ECM proteins represent one of ECM proteins (http://www.matrixome.com/ the earliest recognized and most elaborate bm/Home/home/home.asp, The Matrixome examples of exon (domain) shuffling during Project, maintained by Kiyotoshi Sekiguchi evolution (Engel 1996; Patthy 1999; Hohenester and http://www.proteinatlas.org/;Human Pro- and Engel 2002; Whittaker et al. 2006; Adams tein Atlas) (Ponten et al. 2008; Uhlen et al. and Engel 2007). This characteristic of ECM 2010). A third database (MatrixDB, http:// proteins allows bioinformatic sweeps of the matrixdb.ibcp.fr/) (Chautard et al. 2009, 2010) proteome encoded by any given genome, using collates information about interactions among a list of 50 or so domains to identify a list of ECM proteins. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a004903 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press The Matrisome—An Overview of ECM Constituents COLLAGENS and, in general, collagen subunits are very restricted in the partnerships they can form, Collagens are found in all metazoa and provide although occasional promiscuity has been structural strength to all forms of extracellular noted (for more details, see Ricard-Blum matrices, including the strong fibers of tendons, 2011; Yurchenco 2011). the organic matrices of bones and cartilages, the Some of these genes are viewed as collagens, laminar sheets of basement membranes, the vis- sensu stricto, whereas others that contain only cous matrix of the vitreous humor, and the short collagen segments are often referred interstitial ECMs of the dermis and of capsules to as “collagen-like” or “collagen-related.” The around organs. Collagens are typified by the distinction is to some extent arbitrary because presence of repeats of the triplet Gly-X-Y,where many proteins viewed as “true” collagens also X is frequently proline and Y is frequently 4- contain significant portions made up of other hydroxyproline. This repeating structure forms domains. The original type I collagen of bones stable, rodlike, trimeric, coiled coils, which and tendons consists almost entirely of a long can be of varying lengths. A primordial collagen (1000 amino acids) and rigid uninterrupted exon encoded six of these triplets (18 amino collagen triple helix (plus terminal noncollage- acids) encoded in 54 base pairs and, during evo- nous prodomains that are removed during lution, this original motif has been duplicated, biosynthetic processing of the protein; Fig. modified, and incorporated into many genes 1A). The rodlike trimers assemble into higher- (Fig. 1A). Collagen subunits assemble as homo- order oligomers and fibrils and become cross- trimers or as restricted sets of heterotrimers linked by various enzymatic and nonenzymatic