11 Extracellular Matrix Flashcards
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A large network of proteins and other molecules that surrounds, supports, and provides structure to cells and tissues in the body.
Extracellular Matrix
Which of the following statements is not true for the function/roles of the ECM?
a) cell communication
b) mediation of inflammatory responses
c) enable cells to migrate along intracellular fibers
d) preserve the structural integrity and functional stability of tissues
C.
Migratory abilities within cells are mainly controlled by the cytoskeleton, not the ECM
Components of the ECM
(1) ____ consists predominantly of collagen type IV, laminin, nidogen, and perlecan
(2) ____ is mainly composed of collagen, fibronectin, elastin, etc.
Components of the ECM
(1) Basement Membrane - controls cell organization and differentiation
(2) Interstitial Matrix - under BM
What is one of the most basic structures in the ECM that is also a major component of most connective tissues and the most abundant protein in the body? What is it primarily produced by?
Collagen. Fibroblasts.
What is the structural configuration in which three polypeptide (alpha) chains are wound together to form the long, rigid structure of a typical collagen molecule?
Triple helix
The triple helical structure of a typical collagen molecule forms due to its amino acid composition. What is the repeating sequence of three amino acid residues that make up collagen?
(Gly-X-Y)n
Gly: glycine
X: often proline, can be lysine
Y: often hydroxyproline, can be hydroxylysine
Determine the classifications of collagen according to the structures they’re form:
a. Extensible connective tissue, including skin, lung, vascular system
b. Cartilage, vitreous humor
c. Muscles and most connective tissues
d. Non-cartilaginous connective tissues, including bone, tendon, skin
e. Basement membrane
f. Dermal-epidermal junction
a. Type III
b. Type II
c. Type VI
d. Type I
e. Type IV
f. Type VII
In the synthesis of collagen, the genes coding for pro-alpha chains of collagen are transcribed into mRNAs which are then translated on the rough ER. What precursor facilitates this function?
Preprocollagen
What is the role of the leader/signal sequence in the preprocollagen for the synthesis of collagen?
It is a sequence in the preprocollagen that is responsible for targeting the synthesized polypeptide for secretion from the cell and it is rapidly cleaved in the lumen of the RER, yielding a pro-α chain.
What substance is needed for prolyl/lysyl hydroxylase to hydroxylate proline and lysine?
Vitamin C
TRUE or FALSE. Procollagen contains an extension peptide which contains cysteine residues that allow the formation of intrachain/interchain disulfide bonds, further assisting in the formation of the triple helix. This extension peptide is present in mature collagen.
FALSE. The extension peptide is ABSENT in mature collagen.
What extracellular enzymes remove the extension peptides at both the amino- and carboxy-terminal ends of procollagen to form tropocollagen (monomeric units of collagen)?
Proteinases. Specifically, procollagen aminoproteinase and procollagen carboxyproteinase.
Which copper-dependent enzyme catalyzes the formation of intra- and interchain cross-links to further stabilize the structure of the extracellular matrix?
Lysl oxidase
Despite collagen’s stability, in what conditions is its breakdown increased, and which enzymes are responsible for its degradation?
Collagen breakdown is increased during starvation and inflammatory states. The enzymes responsible for degrading collagen are collagenases, which belong to the matrix metalloproteinase family.
Which inherited disorder is characterized by hyperextensible skin, abnormal tissue fragility, and increased joint mobility due to defects in collagen synthesis and assembly?
Ehler-Danlos Syndorme
What are the three important types of Ehler-Danlos syndrome and their characteristics?
- Hypermobile - Most common type, unknown defect, joint hypermobility
- Classical - Type V collagen abnormality, skin hyperextensibility, generalized joint hypermobility
- Vascular - Most serious type, type III collagen abnormality, fragile blood vessels and organs, tendency for spontaneous rupture of arteries or bowel
Which genetic disorder, also known as hereditary nephritis, results from a defect in Type IV collagen and affects the basement membrane of the renal glomeruli, inner ears, and eyes?
Alport Syndrome
What are the key features and symptoms of Alport syndrome?
- Hematuria (blood in urine)
- Ocular lesions
- Hearing loss
- May develop end-stage renal disease
This is a group of rare inherited skin disorders that causes the skin to be fragile, to break, and to blister easily. It results from the mutations in the gene affecting the structure of Type VII collagen.
Epidermolysis Bullosa
Scurvy is caused by a dietary deficiency of what vitamin?
Ascorbic acid (Vitamin C)
This disease is characterized by bleeding gums, subcutaneous hemorrhages, and poor wound healing caused by a dietary deficiency.
Scurvy
The signs of scurvy reflect defective synthesis of collagen due to reduced activity of what enzymes?
prolyl and lysyl hydroxylases
Both are involved in post-translational modifications which provide rigidity to collagen and require ascorbic acid as a cofactor.
This disease is caused by a deficiency in copper resulting from mutations in the gene for a copper-transporting ATPase. Name the gene involved in this disease.
Menkes Disease caused by mutations in the ATP7A gene or the Menkes protein
Menkes disease causes defective cross-linking of collagen and elastin by what copper-dependent enzymes?
lysl and oxidase
What are the symptoms of Menkes disease?
- Kinky light-colored hair
- Growth retardation
- Red and saggy facial skin
- Low body temperature
- Decreased muscle tone
- Seizures
What is the major protein found in elastic fibers and is responsible for properties of extensibility and elastic recoil in tissues?
Elastin
Where can large amounts of elastin be found?
a. Lungs - would stretch each time breath is inhaled and will return to its original shape with each exhalation
b. Arterial blood vessels - must deform and reform in response to changes in the intravascular pressure
Where can small quantities of elastin be found?
- skin
- ear
- cartilage
What are the properties of mature elastin?
highly insoluble, extremely stable, and has very low-turnover rate
Elastin is synthesized initially as a highly soluble monomer called __________.
tropoelastin
Some proline residues on tropoelastin are hydroxylated via ______________.
prolyl hydroxlase
TRUE OR FALSE. There is a glycosylation step in the lysyl synthesis, followed by the formation of a triple helix.
FALSE. There is no glycosylation step in the lysyl synthesis, nor is there any formation of any triple helix.
This enzyme initiates reactions that cross-link the elastin molecules, eventually forming the mature elastic fibers.
lysyl oxidase
What do you call the major cross-links formed in elastin?
desmosines
What is the significance of the random coil conformation of elastin?
It permits elastin to stretch and subsequently recoil during performance of its physiologic function
A large glycoprotein that is a major structural component of microfibrils.
Fibrillin
These are fine fiber-like strands which provides scaffold for the deposition of philistine in the ECM.
Microfibrils
Which type of fibrillin is the main fibrillin present in adult tissues?
Fibrillin-1
It is an autosomal dominant connective tissue disorder that affects the skeleton, heart and eyes and causes a gene mutation in the FBN1 gene responsible for encoding the protein fibrillin-1. The principal features of the disorder includes tall stature with long extremities, chest wall deformity (pectus carinatum), hypermobile joints (arachnodactyly), long, tapering fingers and toes, predisposition to aortic root, aneurysm rupture or dissection.
Marfan Syndrome
(MarF-ONE for Fibrillin-1 defect)
This refers to the major glycoprotein of the extracellular matrix and an abundant soluble constituent of plasma. It has roles in cell adhesion, migration, growth and differentiation.
Fibronectin
Two types:
1. Insoluble cellular type in ECM
2. Soluble type in plasma
The fibronectin contains ________ sequence which binds to a transmembrane protein. (Hint: The sequence is comprised of three amino acids.)
Arg-Gly-Asp sequence (RGD sequence)
This is the major constituent of the basement membrane (basal lamina) and it consists of three distinct elongated polypeptide chains linked together, forming a complex, elongated shape.
Laminin
Under glomerular filtration barrier (GBM) components, laminin is present with what other components in the basement membrane?
- Type IV collagen
- Nidogen
- Heparan sulfate proteoglycans (HSPG)
The glomerular filtration barrier is comprised of:
- Podocytes
- Glomerular basement membrane (GBM)
- (Capillary) endothelium
This separates the vasculature from the urinary space and is important for filtering excess fluid and wastes out of the blood and into the urine.
glomerular filtration barrier
TRUE OR FALSE. The glomerular filtration barrier has a positive charge barrier that attracts most plasma proteins.
FALSE. It has a negative charge barrier that repels most plasma proteins.
The negative charge barrier is provided by heparan sulfate and it
prevents passage even of plasma proteins that are smaller than the pores present (e.g. albumin).
Unbranched polysaccharides made up of repeating disaccharides
Glycosaminoglycans (GAGs)
2 Main components of GAGs
Amino sugar and uronic acid
GAG that does not contain a uronic acid
Keratan sulfate
GAG that does not contain a sulfate group; made up of N-actelyglucosamine and glucuronic acid
Hyaluronic acid
Which GAG has the ability to attract water and can exist independently as a polysaccharide?
Hyaluronic acid
Which GAG is found in the cornea, cartilage, and connective tissue?
Keratan sulfate
Which GAG is found in the granules of mast cells, liver, lung, and skin and is an important coagulant?
Heparin
Which GAG is found in the kidney basement membrane along with type IV collagen and laminin?
Heparan sulfate
What linkage exists between the xylose and serine residue on the core protein in proteoglycan synthesis?
Glycosidic bond
Inborn errors involving GAGs
Mucopolysaccharidoses
Mucopolysaccharidosis characterized by the defective L-iduronidase
Hurler’s syndrome
Mucopolysaccharidosis characterized by the defective iduronate sulfatase
Hunter syndrome
What permits tumor cells to migrate through the ECM?
Hyaluronic acid
Which GAG can bind LDL and is attributed to atherosclerosis?
Dermatan sulfate
In arthritis and osteoarthritis, the amount of chondroitin sulfate ___ while the amount of keratin sulfate and hyaluronic acid ___.
diminishes; increases
