The extracellular matrix (ECM) is composed of fibrillar and non-fibrillar components. The two main groups of macromolecules that form ECM are fibrous proteins and glycosaminoglycans. The fibrous proteins can be grouped as (i) structural proteins, such as collagens and elastin, and (ii) adhesive proteins, which include fibronectin and laminin.

Collagen, the most abundant protein in the body is predominantly synthesized by fibroblasts; however, epithelial cells may also synthesize small amounts of collagen. The collagen super family includes over 20 different types of collagen with at least 38 distinct polypeptide chains. Of these types I, II, and III are the most abundant and are involved in the formation of fibrils. Type IV collagen forms a two-dimensional reticulum and is a major component of the basal lamina. All collagens contain noncollagenous domains, which perform functions that are distinct from those of the collagen domains. More recently, significant attention has been focused on endostatin, a fragment released from type XVIII collagen, which has been known to block angiogenesis and reduce tumor growth.

Collagens contain a Gly-X-Y repeating structure. The Glycine residue is necessary in every third position to ensure close packaging. Although any amino acid can be present at position X or Y, proline is more frequently found in the X position and hydroxyproline in the Y position. Due to their ring structure, both proline and hydroxyproline stabilize the helical conformation of polypeptide chains. This triplet of amino acids allows collagen chains to twist into a helical structure (a-helix) forming a super helix. Each collagen molecule contains 3 chains twisted around each other to form a triple helix. The 3 chains may either be identical or different depending on the type of collagen. After collagens are secreted in the form of pro-peptides, they are converted to collagen molecules by specific extracellular proteolytic enzymes. The collagens then assemble in the extracellular space to form collagen fibers. Collagen fibers strengthen and help in the organization of the matrix, while elastin fibers provide structural flexibility

Collagens are synthesized as longer precursor proteins called procollagens. Collagen fibers begin to assemble in the endoplasmic reticulum and Golgi complexes. Here the signal sequence is removed and specific proline and lysine residues are hydroxylated. Prolyl hydroxylase converts proline residues to hydroxyproline in the endoplasmic reticulum. Lysine residues in collagen are also frequently converted to hydroxylysines by lysyl hydroxylase. The OH groups of these modified amino acids help in stabilizing the collagen triple helix by forming hydrogen bonds between polypeptide chains. Following completion of this processing, procollagens are secreted into the extracellular space where extracellular enzymes remove the pro-domain. The collagen molecules then polymerize to form collagen fibrils. Oxidation of specific lysine residues by lysyl oxidase forms reactive aldehydes that are involved in the formation of specific cross-links between two chains. This process helps in stabilizing collagens in the fibril. In type IV collagen, found in basal lamina, the Gly-X-Y repeats are frequently interrupted by nonhelical sequences that allow greater flexibility than seen in fibril-forming collagens.

The critical role of collagens is evident from a wide spectrum of diseases resulting from hundreds of known mutations in 22 genes for 12 different collagen types. Defects in the synthesis and degradation of collagen and elastin contribute to a number of diseases. Some of the well-known collagen related diseases include osteogenesis imperfecta, many chondrodysplasias, some cases of osteoporosis, and several subtypes of the Ehlers-Danlos syndromes. The adhesive proteins assist cells to attach to the extracellular matrix. For example, fibronectin, a large dimeric glycoprotein, promotes the attachment of fibroblasts and other cells to the matrix in connective tissue. It interacts with a wide variety of proteins, including collagen, heparin, fibrin, gelatin, DNA and cell-surface receptors of integrins. Fibronectins can also regulate the shape of cells and organize cytoskeleton. Fibronectins bind extracellular matrix proteins through a tripeptide arginine-glycine-aspartic acid (RGD) sequence.

By facilitating the migration of immune cells to the site of injury fibronectins play an important role in wound healing. They bind to integrins on platelets via RGD domains and cause localization of platelets to the site of injury. They also bind to fibrin and assist in blood clotting. Other adhesive molecule, such as laminin, promote the attachment of epithelial cells to the basal lamina. Laminin is a hetrotrimer, consisting of A (400 kDa), B1 and B2 subunits (200 kDa each). Each subunit contains at least 12 repeats of EGF-like domains. The number of EGF repeats varies between different species. Laminin also stimulates spreading of many cell types and promotes the outgrowth of neurites in culture.