Extracellular Matrix Flashcards
(34 cards)
What is the extracellular matrix?
Extracellular matrix (ECM) is a complex network of macromolecules (proteins and carbohydrates) deposited by cells, made up of both fibrillar and non-fibrillar components. After being deposited, it becomes immobilized outside the cells and it fills in the spaces between cells.
What is ECM essential for?
Development, Tissue function, Organogenesis. ECM plays both architectural (mechanical stability) and instructional roles (influences cell behaviour). Key functions of the ECM are: Provide physical support; Determine the mechanical and physicochemcial properties of the tissue; Influence the growth, adhesion and differentiation status of the cells and tissues with which it interacts.
What do connective tissues contain?
Connective tissues are particularly rich in extracellular matrix. All connective tissues contain a complex spectrum of collagens, multiadhesive glycoproteins and proteoglycans (extracellular matrix) together with a cellular component.
What are the varieties of extracellular matrix components?
Collagens - e.g. Type I, II, III (fibrillar), Type IV (basement membrane).
Multi-adhesive glycoproteins - e.g. Fibronectin, Fibrinogen, Laminins (basement membrane).
Proteoglycans - e.g. Aggrecan, Versican, Decorin, Perlecan (basement membrane)
How is connective tissues with various properties generated?
Different types of collagen and different arrangements of oriented collagen, coupled with the presence or absence of different ECM components, generates a wide variety of connective tissues with the varied properties required for function.
What is collagen?
These are a family of fibrous proteins found in all multicellular organisms. They are the most abundant proteins in mammals, constituting up to 25% of the total protein mass. Collagens are the major protein components of bone, tendon and skin, with at least 28 different collagen types existing in humans, denoted by Roman numerals. The different collagen components are encoded by 48 different genes.
What is each collagen molecule made of?
Each collagen molecule is made up of three α chains and can be a homotrimer or a heterotrimer.
Type I collagen has chains from two genes. It is a heterotrimer with the composition [α1(I)]2 [α2(I)]
Types II and III collagen are homotrimers, having only one chain type. Their compositions are therefore, [α1(II)]3 and [α1(III)]3.
The α chains form a triple helix. In fibrillar collagens, each α chain is approximately 1000 amino acids long, forming a left-handed helix. The primary sequence of collagen proteins contains a characteristic glycine-x-y repeat where x is often proline and y is often hydroxyproline. To form a stiff triple helical structure, every third position in the must be occupied by the amino acid glycine, as this is the only amino acid small enough to occupy the interior.
Describe hydrogen bond formation between collagen molecules
Just as proline undergoes a post-translational modification of hydroxylation, lysine and hydroxylysine are similarly modified in the formation of covalent cross linkages. This contributes to interchain hydrogen bond formation. hese provide tensile strength and stability. Both lysine and hydroxy-lysine residues are involved. Crosslinking only takes place only after the collagen has been secreted.
What is the impact of a vitamin C deficiency?
Vitamin C-deficiency results in underhydroxylated collagens, with dramatic consequences for tissue stability (scurvy). This is due to the enzymes prolyl hydroxylase and lysyl hydroxylase requiring vitamin C as a co-factor for functionality.
How does collagen biosynthesis work?
Collagen biosynthesis and secretion follows the normal pathway for a secreted protein. However, the collagen α chains are synthesised as longer precursors, called pro-α chains, by ribosomes attached to the endoplasmic reticulum. The pro-α chains undergo a series of covalent modifications and fold into triple-helical procollagen molecules, before their release from cells.
What are the steps in collagen biosynthesis?
Pro-a chains in ER Procollagen Cleavage of propeptide Collagen Fibril formation Cross linking
How are fibrils formed and what is their purpose?
Some collagens are fibril-associated and regulate the organisation of collagen fibrils in tissues. Staggered arrays of tropocollagen molecules form fibrils, which ultimately arrange to form collagen fibres. Tensile strength is provided by the fibres being in parallel bundles - these resist tensile force in one direction.
What is Ehlers–Danlos syndromes?
Group of inherited connective tissue disorders whose symptoms include stretchy skin and loose joints. Several of these can arise due to mutations in collagen, which negatively affect collagen production, collagen structure or collagen processing.
What are non-fibril forming collagens?
Not all collagens form fibrils. An important non-fibrillar collagen is the network forming collagen type IV, which is present in all basement membranes. In the collagen IV network, the collagen type IV molecules can associate laterally between triple-helical segments as well as head-to head and tail-to tail between the globular domains to give dimers, tetramers and higher order complexes.
What are basement membranes?
These are flexible, thin mats of extracellular matrix underlying epithelial sheets and tubes. Basement membranes surround muscle, peripheral nerve and fat cells and underlie most epithelia. They are highly specialized extracellular matrices containing a distinct repertoire of collagens, glycoproteins and proteoglycans.
Where is the basement membrane in the kidney and what pathologies can this cause?
In the kidney, they form a key part of the filtration unit as the Glomerular basement membrane (GBM).
DIABETIC NEPHROPATHY - accumulation of ECM in restricting renal filtration. In the disorder diabetic nephropathy, there is an accumulation of extracellular matrix leading to a highly thickened basement membrane. This restricts renal filtration and can lead to renal failure.
ALPORT SYNDROME - mutations in collagen IV leading to split GBM affecting kidney and hearing. In Alport syndrome, mutations in collagen IV result in an abnormally split and laminated GBM which is associated with a progressive loss of kidney function and also hearing loss.
What are elastic fibres?
Whereas collagens are important for the tensile strength of tissues, elastic fibres are important for the elasticity of tissues, such as skin, blood vessels and lungs. Often, collagen and elastic fibres are interwoven to limit the extent of stretching.
Elastic fibres consist of: A core made up of the protein elastin and Microfibrils, which are rich in the protein fibrillin.
What is fibrillin and what is an associated pathology?
The integrity of elastic fibres depends upon microfibrils, containing the protein fibrillin.
MARFAN’S SYNDROME
Mutations in the protein fibrillin-1 are associated with Marfan’s syndrome which has some diverse manifestations, involving primarily the skeletal, ocular, and cardiovascular systems. Individuals can be predisposed to aortic ruptures.
What is elastin?
Elastin is an unusual protein consisting of two types of segments that alternate along the polypeptide chain: hydrophobic regions, and alpha-helical regions rich in alanine and lysine. Many lysine side chains are covalently cross-linked.
What is the nature of ECM proteins?
Most ECM proteins are very large. They have a modular architecture; i.e. they are composed of characteristic protein domains of 50-200 amino acids.
The multifunctionality of ECM proteins is a result of their modular structure. Many large modular proteins are multi-adhesive, binding various matrix components and cell-surface receptors.
What are laminins?
Laminins are heterortrimeric proteins made up of an α chain, a β chain and a γ chain, which form a cross shaped molecules as shown below. Laminins are very large proteins with each chain having a molecular weight of between 160 and 400 kDa. Are multi-adhesive proteins which can interact with a variety of cell surface receptors including integrins and dystroglycan. They can self-associate as part of the basement membrane matrix, but can also interact with other matrix components such as type IV collagen, nidogen and proteoglycans.
What is a pathology related to mutation in laminins?
MUSCULAR DYSTROPHY // EPIDERMOLYSIS BULLOSA
Mutations in specific chains are associated with inherited diseases such as muscular dystrophy and epidermolysis bullosa. Congenital muscular dystrophy can arise from an absence of the α2 chain in laminin 2. Symptoms include hypotonia (abnormally decreased muscle tension), a generalised weakness and deformities of the joints.
What are fibronectins?
Fibronectins are a family of closely related glycoproteins of the extracellular matrix which are also found in body fluids. They can exist either as an insoluble fibrillar matrix or as a soluble plasma protein. They are derived from a single gene, with alternate splicing of mRNAs giving rise to the different types.
What are the properties of fibronectins?
Fibronectins are multi-adhesive proteins, made up of a large multidomain molecule linked together by disulphide bonds. fibronectins are able to interact with cell surface receptors and other matrix molecules. They play important roles in regulating cell adhesion and migration in a variety of processes, notably embryogenesis and tissue repair. They are also important for wound healing, helping to promote blood clotting (ALS2 - Haemostasis). Fibronectins form a mechanical continuum with the actin cytoskeleton of many cell types. Integrin receptors at the cell surface provide the linkage between the matrix and cytoskeleton.
