by dbui89

Bookmark and Share

Front Back
3 Classes of Biomolecules in the extracellular matrix
Proteoglycans, Structural proteins (collagen, elastin, and fibrillin), and specialized proteins (Fibronectin and laminin)
Major component of the ECM, can interact with proteins in the ECM. 
Consists of a core protein covalently attached to long, linear chains of glycosylaminoglycans. 
Occupy a large space, acting as a "molecular sieve" and providing some flexibility to substances such as cartilage.
Structurally resembles a bottlebrush, with many glycosaminoglycan chains extending from the core protein
Long, linear chains made up of repeating disaccharide subunits. At least seven types which differ in repeating disaccharide subunits.
Attached to proteins by covalent linkages to serine or threonine residues (except keratan sulfate I which attaches to an asparagine residue and hyaluronic acid which attaches through noncovalent linkages).
7 types of glycosaminoglycans
Chondroitin sulfate
Dermatan sulfate,
Heparin sulfate
Hyaluronic acid
Keratin Sulfate I
Keratin Sulfate II
How is a glycosaminoglycan synthesized?
Once the protein enters the ER, glycosaminoglycan synthesis begins with the attachment of a UDP-linked sugar to serine, threonine or asparagine (only in the case of keratin sulfate I). 
Specific UDP-sugar glycosyltransferases will transfer monosaccharides to an appropriate acceptor (serine, threonine, asparagine residues, or the last sugar of the growing chain).
After the initial linking sugar is added on, repeating disaccharide units are added.
3'phophoadenosine 5' - phosphosulfate (PAPS) provides sufate groups for N- and O- sulfation of glycosaminoglycans.
Sulfation of the glycosaminoglycans makes them negatively charged, causing them to repel each other, leading to the bottlebrush structure of proteoglycans.
Describe how proteoglycans interact
Hyaluronic acid can form noncovalent interactions with core protein of a proteoglycan, forming an aggregation of multiple proteoglycans attached to the hyaluronic acid.
Proteoglycans can interact with fibronectin, which is attached to Integrin, an integral protein. Cross-linked fibers of collagen also associate with this complex, forming the extracellular matrix.
Similar to Proteoglycans, however, several distinct differences. Has shorter sugar chains not made of repeating disaccharide subunits. The active parts is the protein part rather than the sugar chains as in proteoglycans.
Synthesis begins through O-linkages (serine or threonine) or N-linkages (asparagine). 
O-linked synthesis of Glycoproteins
Begins with attachment of N-acetyl-galactosamine onto a specific serine or threonine at the hydroxide group of the side chains. Very similar to attachment of glycosaminoglycans to proteoglycans.
Glycoproteins destined for the plasma membrane will integrate into the golgi membrane, those mean to be secreted remain free in the lumen and bud off.
N-linked synthesis of Glycoproteins
Rather than add a sugar one at a time, the entire sugar chain is added at once through transfer from a lipid-linked oligosaccharide (dolichol).

Dolichol has an oligosaccharide containg N-acetylglucosamine, mannose, and glucose attached to it through a pyrophosphate linkage.

Sugars are added to the chain by glycosyltransferases. As the chain finishes a protein-oligosaccharide transferase enzyme transfers the sugar chain to the asparagine residue of the glycoprotein.
A membrane-bound lipid that is used to facilitate the transfer a glycosidic chain onto a protein in N-linked glycoprotein synthesis.
How are proteoglycans and glycoproteins degraded?
Both are brought into the cell by endocytosis and degraded by lysosomal enzymes. Glycosidases degrade the carbohydrate portion.
A lysosomal enzyme that degrades carbohydrate chains by cleaving them into shorter oligosaccharides.
A lysosomal enzyme that degrades carbohydrate chains by cleaving the sugar linkages from the nonreducing end of the chain.

Very specific, multiple types of exoglycosidase, each specific for a certain type of linkage.
Describe the structure of collagen
Triple helical structure, it can make up the entirety of the collagen or in some it can be just a small portion.
Collagen subunits join together to form alpha helical chains. Glycine is present in every third residue of these chains, leading to its very compact structure (4 residues per turn of the helix). About 100 of the second and third residues are proline and hydroxyproline respectively. Both increase the rigidity of the collagen.
Three of these chains twist together to form a left-handed superhelical structure stabilized by hydrogen bonds.
How is collagen synthesized?
Initially synthesized as preprocollagen which contains a signal sequence removed in the ER and a polypeptide extension at it's N- and C-terminals. These extensions help the collagen form into its triple helical structure, winding from the C-terminus towards the N-terminus.
What is the function of Polypeptide Extensions in Collagen
25-30 kDa in length, these extensions are present on both the N- and C- terminus of collagen alpha hellicies. Both contain cysteine residues, which allow for interchain disulfide bonds. The C-terminal extension is capable of intrachain disulfide bonds, which helps keep the collagen helices together as they wind into their superhelical structure.
Prolyl hydroxylase
Enzyme that hydroxylates proline to form the hydroxyproline in the Y position of collagen. Occurs post-transcriptionally by hydroxylation of proline residues. Requires ascorbic acid (Vitamin C) and alpha-ketoglutarate as cofactors.
Lysyl Hydroxylase
Enzyme that hydroxylates lysine residues to form hydroxylysine, which can participate in the Y position of collagen's amino acid chain. Requires cofactors similar to those of Prolyl hydroxylase.
What happens when there are stretches of collagen protein that lack the Gly-X-Y repeat sequences?
Interruptions of the triple helix occur, resulting some areas having a globular structure interspersed in the triple helical structure. This can be seen in Collagen IV (basement membrane).
Types of Cartilage we need to know
Type I forms collagen bundles visible under light microscopy, most abundant collagen in the body. Found in skin, bone, tendon, blood vessels, cornea. Type II does not form bundles, but do form collage fibrils. Found in cartilage , intervertebral disks, and vitrous humour of the eye. Type IV, does not form bundles, contains globular areas interspersed in the triple helical structure. Found in the basement  membrane.
Ehlers-Danos Syndrome
Inherited disorders which normally feature hyperextensibility of the skin, abnormal tissue fragility, and increased joint mobility.
Alport Syndrome
Genetic abnormalities affecting Type IV fibers. Patients have red blood cells in urine (hematuria). Causes abnormalities in renal basal membrane, can lead to end-stage renal disease.
Vitamin C deficiency, prolyl hydroxylase and lysyl hydroxylase cannot function without it, affects structure of collagen. Major signs are bleeding gums, subcutaneous hemorrhages, and poor wound healing.
Connective tissue responsible for the extensibility and elastic recoil in tissue.
Synthesized as a tropoelastin molecule, there is some prolyl hydroxylase activity. Unlike collagen formation, there are no polypeptide extensions. There is no Gly-X-Y arrangement, no triple helical structure.
Once secreted from the cell, lysyl residues of the tropoelastin are deaminated to aldehydes by lysyl oxidase 
The major cross-links of elastin. Formed by three lysine-derived aldehydes with an unmodified lysine. This cross-link is unique to elastin and makes extracellular elastin highly insoluble and very stable with a low turnover rate.
Williams Syndrome
Deletions in elastin gene, developmental disorder affecting connecting tissue and CNS. Many patients are affected by supravalvular aortic stenosis.
Large glycoprotein, structural component of microfibrils. Secreted into the ECM by fibroblasts, forms microfibrils, becomes insoluble, acts as a scaffold for elastin to attach to.
Marfan Syndrome
Autosomal dominant disease affecting connective tissue (eyes, skeletal system). Caused by mutations in fibrillin genes. Patients are tall, exchibit arachnodactyly, hyperextensibility, and cardiovascular problems.
Soluble glycoprotein found in large amounts in the ECM. Dimer joined by disulfide bonds near the C-terminus.
Acts as an adhesion molecule, contains seven binding sites for heparin, fibrin, college, DNA and cell surface proteins (fibronectin-receptor an integral receptor protein of the integrin class).
Contains an Arg-Gly-Asp sequence that binds to integrin.
Formed by 3 distinct elongated polypeptide chains linked together to form a cruciform shape. Binding sites for type IV collagen, heparin, and integrin on the cell surface.
Is a primary component of the basal lamina of the basement membran.
x of y cards