Extracellular Matrix Flashcards
What are the types of ECM proteins?
Proteoglycans
Structural proteins like collagen, elastin, fibrillin
Specialiazed proteins like fibronectin and laminin
Where are proteoglycans found?
Synovial joints (compressibility properties)
Vitreous humor of the eye
Arterial walls (strength)
Bone and cartilage
What are the types of interactions proteoglycans do?
Interact with:
Collagen and elastin-play structural role
Fibronectin-involved in cell adhesion and migration
Laminin-found in basal laminae such as the renal glomerulus
What is the structure of the proteoglycans?
Core protein
Covalently attached long, linear chains of glycosaminoglycans which are repeating disaccharide units (hexosamine+uronic acid)
Frequently sulfated
Negatively charged and repeal each other
Act as a lubricant
Occupy large space
Act as molecular sieves-Control which substances approach and leave the cell
Give flexibility to cartilage for compression and re expansion
What are the type of proteoglycans?
7 which differ in the monosaccharides present in their repeating disaccharide units Hyaluronic acid Chondroitin sulfate Dermatan sulfate Heparin Heparan sulfate Keratan sulfate I and II
How is the binding of proteoglycans?
All proteoglycans are attached to protein by covalent linkage to serine or threonine residues
Keratan sulfate I is attached via asparagine residue
Hyaluronic acid binds to proteins through non covalent linkage
What is the process for synthesis of proteoglycans?
Synthesis start with the attachment of a sugars to a serine or threonine residues once a core protein enters the lumen of the ER
UDP-sugars are the substrate for synthesis
Specific UDP-sugar glycosyl transferases are responsible for sequential transfer of monosaccharides
Synthesis starts with linking sugar synthesis
Once the linking sugars are attached, 2 alternating glycosyltransferases add the sugars of the repeating disaccharide to the growing glycosaminoglycan chain
What is the process of sulfations of proteoglycans?
Sulfate groups attached through N or O-sulfation
Occurs after addition of sugars
3’-phosphoadenosine 5’-phosphosulfate (PAPS) provides the sulfate groups.
Only way sulfate is actively transfer in biological system is through PAPS
What are the function of proteoglycans?
Hyaluronic acid-cell migration, embryogenesis, morphogenesis, wound healing
Chondroitin sulfate-formation of bone, cartilage and cornea
Keratan sulfate-Transparency of cornea
Dermatan sulfate-Transparency of cornea, binds LDL to plasma wall
Heparin- Anticoagulant , binds to antithrombin III, releases lipoprotein lipase from capillary wall
Heparan sulfate-Component of skin fibroblast and aortic wall, commonly found on cell surface
What is the structure of the glycoproteins?
Contain much shorter carbohydrates
Carbohydrate moiety is branched and is not made of repeating disaccharides
Most plasma proteins in the blood are glycoproteins
What is the process of glycoproteins synthesis?
Carbohydrate chains are added in the lumen of ER and the Golgi
The initial sugar is added to the serine or threonine residues for O-linkage and asparagine residues for N-linkage
Carbohydrate chain is extended by the sequential addition of suga residues to the non reducing end
What are the 2 types of oligosaccharide synthesis ?
O linked
N-linked
What is the process of. Synthesis of O-linked glycosides?
Glycosylation begins with the transfer of N-acetylgalactosamine onto a specific serine or threonine
Glycoproteins destined to the plasma membrane will be integrate to the Golgi membrane with glycosyl moiety facing the Golgi lumen
Glycoproteins secreted from the cell remain freee in the lumen
Secondary vesicles bud off from the Golgi and fuse with the cell membrane releasing glycoproteins to the extracellular space
What is the process of N-linked glycosides?
Initially protein does not become glycosylation with individual sugars
Instead a lipid linked oligosaccharide is first constructed
Sugars are added to the dolichol by the membrane bound glycosyltransferases
Oligosaccharide is transferred from the dolichol to an asparagine side group of the protein by a protein oligosaccharide gtransferase enzyme present in the ER
What is the process of degradation of proteoglycans and glycoproteins?
Proteoglycans and glycoproteins are brought inside the cell by endocytosis
They are degrade by lysosomal enzymes
The carbohydrate moiety is degraded by glycosidases
Lysosomes contains endoglycosidases and exoglycosidases
Endoglycosidases cleave carbohydrate chains to shorten oligosaccharides
Exoglycosidases specific for each type of linkage remove the sugar residue from the non reducing end
What is the structure of the collagen?
Triple helical structure
Each polypeptide is twisted into a left handed twist into a left handed helix of 3 residues per turn
Helix structure stabilizes by hydrogen bonding
Glycine residues occur at every 3 position of the alpha chain
Repeating structure of Gly-X-Y
Prolines and hydroxyprolines increase rigidity of the collagen molecule
How is the process of synthesis of collagen?
Collagen is synthesized as a preprocollagen
Contains a leader or signal sequence which is removed in the ER
Some hydroxylysines residues are further modified by the addition of galactose through an o-glycoside linkage
No further modification occurs after formation of triple helix
Examples of nonhelical collagens
Several collagen do not form fibrils
Example collagen 4
Characterized by interruptions of the triple helix with stretches of protein lacking Gly-X-Y repeats
What are some genetic diseases of collagen synthesis?
Ehlers-Danlos Syndrome
Alport syndrome
Scurvy
What are the characteristics of Ehlers-Danlos Syndrome?
Group of genetic diseases with hyperextensibility of the skin, abnormal tissue fragility and increased joint mobility
Several types
Type 4- most serious due to the tendency for spontaneous rupture of arteries or the bowel
Type 6 due to deficiency of Lysol hydroxylase. Patients exhibits marked joint hypermobility and tendency to ocular rupture
Type 7C-deficiency of N proteinase causing formation of abnormal thin, irregular collagen fibrils manifested by marked joint hhypermobility
What are the characteristics of the Alport syndrome?
X linked or autosomal genetic disease affecting type 4 collagen
Patients are presented with hematuria and may eventually develop end stage renal disease
What are the characteristics of Scurvy?
Due to deficiency of ascorbique deficiency necessary for cross linking of collagen structure
Major signs are bleeding gums, subcutaneous hemorrhages and poor wound healing
Signs reflect deficiency of prolly and Lysol hydroxylase.
What is the characteristics of the elastin?
CT protein
Responsible for tissues extensibility and elastic recoil
Give tissues and organs the capacity to stretch without tearing
Synthesized in a single tropoelastin molecule
Does not have hydroxylysine or glycosylated hydroxylysine
Have no extension peptides
Have no Gly-X-Y arrangement and no triple helical structure
Major cross links are desmosines(3 oxidized lysine + non modified lysine)
Cross links highly insoluble and extremely stable with very low turn over
What is the characteristics of Williams Syndrome?
Elastin gene deletions found in 90% of patients
Development disorder affecting the CT and the CNS
May result in the supravalvular aortic stenosis
What are the characteristics of the fibrillin?
Large glycoproteins Structural component of microfibrils Found in many tissues Secreted into ECM by fibroblasts Incorporated into the insoluble microfibrils which appear to provide scaffold for deposition of elastin
What are the characteristics of Marfan Syndrome?
Autosomal dominant disease affecting CT
Due mostly to fibrillin mutations
Most patients are tall and exhibit long digit (arachnodactyly)
Hyprextensibility of joints, cardiovascular system
What are the characteristics of Fibronectin?
Soluble glycoproteins found in large amount in ECM
V shape
Consist of 2 peptide chains joined by disulfide bonds
Contains 7 domains binding to heparin, fibrin, collagen, DNA and cell surfaces
Cell fibronectin-receptor belongs to family of transmembrane integrin proteins
Fibronectin receptors contains Arg-Gly-Asp (RGD) sequence that binds to integrin
What are the characteristics of the laminin?
Consists of 3 distinct elongated poly[peptide chains link together to form an elongated cruciforme shape (cross shape)
Has binding sites for type 4 collagen, heparin and integrin
