42 terms

C&T: Extracellular Matrix

Objectives: 1) Define extracellular matrix, list the major groups of compounds that are in the extracellular matrix, and list functions of the ECM. 2)Describe the 4 main categories of collagens, know examples of each, and understand how they differ in structure and function. 3) Discuss the general properties of the collagen polypeptide chain: amino acid composition and secondary and tertiary structure. 4) Describe the various steps in collagen synthesis, where they take place and what the key en…
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Extracellular Matrix
- Network of macromolecules that occupy space not occupied by cells:
- Made of insoluble fibers and soluble fibers
- Roles: 1) scaffold to stabilize, but are also dynamic with turnover; 2) influences survival, development, proliferation, migration and function of cells
- Produced by: fibroblasts, osteoblasts, and chondrocytes
Collagen
This insoluble fibrous macromolecule is a major structural protein family in ECM
- typically triple-stranded helical structure
- proline and glycine rich
- 25% of protein mass

Structure
- Gly-X-Y in left handed helix (A)
- X= proline (30%), Y=hydroxylysine or hydroxylproline
Outside (H-bonds)
In the right handed triple helix, one could find proline and hydroxyproline in this part of the helix. (*Bonus: this is the significance of the location of X and Y)
Glycine (inside)
Mutation in this amino acid would result in a triple helix that does not wrap tightly.

(Bonus: this is the location of the amino acid)
FACIT Collagen (Type IX)
This family of collagen includes fibril associated collagens with interrupted triple helices. These collagens link fibrils to one another and other ECM macromolecules. (Bonus: this is the type of collagen that binds to type two collagen)
Network-forming Collagen (Type IV)
This category of collagen has an interrupted triple helix that forms a flexible meshy sheet-like multi-layered network with many associations, especially in the BASAL LAMINA (Bonus: this category of collagen is exemplified by this type of collagen)
Fibril-forming Collagen (classic EDS)
This category of collagen is found in the interstitial tissues. There are several associations:
Type 1 - bone, tendon, dermis, cornea, dentin
Type 2 - cartilage
Type 3 - reticular fibers of most tissues (lung, liver, dermis, vessel walls)
Type 5 - fetal tissues, placenta, skin, interstitial tissues

(Bonus: this is the disease that results from a mutation in the type 5 collagen)
Anchoring Collagen Filaments- (Type VII)
This category of collagen is found beneath the basal lamina. Its function is to connect the basal lamina to the underlying connective tissue.

As pictured, defects in this collagen results in blistering diseases, like dystrophic epidermolysis bullosa (DEB), where the skin raises from the lamina.

(Bonus: In this category, this is the major type of collagen that we learned)
ER and Golgi (Vit C)
In the first steps of collagen synthesis, pro-alpha chain is made here. Then these helices must have post-translational modifications, including hydroxylation and glycosylation, before lining up to form the triple helix. These steps occur in this organelle(s) of the cell.

Bonus: this is the source of hydroxylation of proline and lysine.
ER
The procollagen triple helix forms in this part of the cell and then is secreted from the cell.
procollagen, tropocollagen, fibril, collagen fiber
These are the steps of collagen formation outside of the cell:

__________ --N,C proteinase cleaves propeptide--> __________ --lysyl oxidase forms crosslinks--> __________ --aggregation--> _________ ________
Propeptide (Procollagen N,C-proteinase)
Until the later steps in collagen synthesis, this structure helps form disulfide bonds and maintains solubility.

(Bonus: these enzymes cleave this structure in the later steps leading to its insolubility)
Collagen fibril (tropocollagen)
Structure number 1 is known as this.

(Bonus: number 2 is known as this)
Lysyl oxidase (copper)
The inter-/ intramolecular crosslinks between and within tropocollagen are formed by this enzyme. These crosslinks increase strength of the cumulative collagen fibril strand.

(Bonus: this enzymes depend on this cofactor)
Osteogenesis Imperfecta (AutoD)
This type 1 collagen disease is known as "the brittle bone disease", but it has wide symptoms in the bone, tendon, dermis, etc.

(Bonus: this is the pattern of inheritance)
Stickler Syndrome
This type 2 collagen disease affects the cartilage and vitreous humor and results in distinctive facial appearance, eye abnormalities, hearing loss, and joint problems.
Vascular Ehlers-Danlos Syndrome
This type 3 collagen disease affects the reticular fibers of most tissues. Due to abnormal collagen fibers, the patient may present with fragile stretchy skin and aortic or intestinal rupture. Very dangerous to have a vaginal birth with this disease.
Alport Syndrome
This type 4 collagen disease has abnormalities in the sheets of basal lamina. This results in defects in basal lamina of kidney --> leakage: blood and protein in urine; kidney failure; hearing loss. Also known as, "basement membrane defect"
Classic Ehlers-Danlos Syndrome
This type 5 collagen disease has abnormalities in the dermis and interstitial tissues. In some patients, it is easily defined by overly stretchy skin and wide healing scars.
Dystrophic Epidermolysis Bullosa (DEB)
This type 7 collagen disease has abnormalities in the soft tissues, derm-epiderm junction due to defects in the type VII collagen.

Do not confuse with EB Simplex, which has a defect in keratin (and looks like less intense blisters)
Elastin (fetal and juvenile fibroblasts)
This insoluble fibrous macromolecule provides the resilience (stretch) of the skin, vessels, and ligaments by associating with collagen fibers to limit stretching and preventing tearing. It is highly hydrophobic (proline and glycine), is not glycosylated or "hydroxylized". It has many crosslinks at the lysine residues to stablize the fibers.

(Bonus: this makes the molecule)
Fibrillin (Marfan syndrome)
The elastic fiber is made of two alternating segments of hydrophobicity and alpha-helical segments (alanine/ lysine --> crosslinks)

Elastin is bound in fibers of microfibril sheaths. The sheaths are composed primarily of this protein.

(Bonus: Defect in this protein may result in this disease)
Adhesive proteins and Polysaccharides +/- protein
These are the two types of soluble macromolecules.
Adhesive glycoprotein (Arg-Gly-Asp)
This family of soluble macromolecules act as domains for binding to cell surface receptors and other ECM molecules. These receptors recognize specific, short, peptide seq on adhesive proteins. They may form oligomers through disulfide bonds and nonconvalent self-self association. Highly diverse due to splicing/ gene duplication and local regulation.

(Bonus: This is their repetitive structural unit.)
Fibronectin (blood clotting)
This example of an adhesive glycoprotein is found in most ECM and plasma. It binds to collagen and proteoglycans. Type III module contains RGD sequence for binding receptors. Importantly, it exists as a protein dimer, consisting of two nearly identical monomers linked by a pair of disulfide bonds.

(Bonus: these proteins are found in this aspect of inflammation)
Alternative Splicing (Adhesion and migration)
Although Fibronectin is produced from one gene, it has highly diverse isoforms due to this mechanism in pre-mRNA.

Examples:
- Soluble plasma fibronectin - component of blood plasma made by liver
- Insoluble cellular fibronectin - component of ECM.

(Bonus: these are the major roles of fibronectin)
Laminin (Blue sword)
This is a large adhesive glycoprotein that is a major component of BASAL LAMINA. It has binding domains specific for other actors in the BL, including type IV collagen, heparin sulfate (perlecan), enactin (nidogen), and integrins. It consists of 3 poly peptide chains: aplpha, beta, gamma (made by A, B1, B2 genes)

(Bonus: in this picture, this is the color and shape of the adhesive glycoprotein in question)
type IV collagen
This is the primary component of the basal lamina.
Integrin
This glycoprotein is a cell receptor that interacts with the surrounding ECM, providing anchor for the cell to the matrix of the collagen + links to peptidoglycans.
Basement Membrane (Type VII)
This includes the basal lamina and the underlying collagens.

(Bonus: this is the type of collagen that anchors basal lamina to the reticular fibers)
Glycosaminoglycan (GAG)
This is a long unbranched sugar chain that is characterized by polarity and extended chains. It creates large volume relative to their mass due to attraction of water in the space, which creates a compressive force (JOINTS).
Glycosaminoglycans (skin, vitreous body, cartilage, synovial fluid)
Hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate are examples of these.

(Bonus: this are the tissues made of hyaluronon)
Hyluronan (1)
These GAGs are made of glucoronic acid and N-acetylglucosamine. They are much larger, simpler, and not covalently attached to protein. Their site of production is unique as it can be made on the cell surface.

(Bonus: in the picture, this number points to the protein in question)
Proteoglycan
These are core proteins (made on the rER) with sugars attached (in Golgi). They have >100 GAG chains, which can be of various GAG types. Their main functions are to immobilize and restrict movement, sterically block activity, protect from degradation, etc.
Aggrecan
This is a major macromolecule of cartilage (made of several GAGs). Due to extensive hydration, it creates a gel-like matrix. These proteoglycans require a core of Hyaluronan
Aorta (vascular EDS)
Looking at amount and characteristics of the constituents, number 3 represents which tissue.

(Bonus: defect in the collagen of this area results in this disease)
Fibrillar collagen
Tissues that withstand tensional force need high levels of this.
Proteoglycan
Tissues that withstand compressive force need high levels of this.
Integrin
This transmembrane cell receptor is made of alpha and beta subunits that function in cell signaling (depend on extracell divalent cations) and the regulation of cell cycle, shape, and motility through LINKING the ECM with the actin cytoskeleton.
Hyaluronic acid
This GAG is involved in the granulation tissue stage of would healing from the extracellular matrix.
Hydroxylysine glycosides, pyridinium cross links, telopeptides (Extracellular degradation)
One could look in the urine for elements that indicate collagen degradation of the bone by osteoclasts.

(Bonus: name the type of degradation in this example)
Matrix Metalloproteinases (MMP)
These extracellular endopeptidases selectively degrade components of the ECM, such as collagenases, elastases, and proteinases. They are dependent on zinc ion. Also secreted in latent form so need activation from other endopeptidases.

Thought to play a role in cancer progression as ECM-degrading enzymes help metastasis by breaking down barriers.

They are inhibited by chelating agents, tetracycline and TIMPS --> cancer therapy?
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