- Most abundant protein in the human body.
- Extensively modified by posttranslational modification.
- Organizes and strengthens extracellular matrix.
- Type I
- Most common (90%)—Bone (made by osteoblasts), Skin, Tendon, dentin, fascia, cornea, late wound repair
- Type I: bone.
- Type I
- ↓ production in osteogenesis imperfecta type I.
- Type II
- Cartilage (including hyaline), vitreous body, nucleus pulposus.
- Type II: cartilage.
- Type III
- Reticulin—skin, blood vessels, uterus, fetal tissue, granulation tissue.
- Type II
- Type III: deficient in the uncommon, vascular type of Ehlers-Danlos syndrome (ThreE D).
- Type IV
- Basement membrane, basal lamina, lens.
- Type IV: under the floor (basement membrane).
- Defective in Alport syndrome
- targeted by autoantibodies in Goodpasture syndrome.
Collagen synthesis and structure
- Inside fibroblasts
- Synthesis (RER)
- Translation of collagen α chains (preprocollagen)—usually Gly-X-Y (X and are proline or lysine).
- Glycine content best reflects collagen synthesis (collagen is 1⁄3 glycine).
- Hydroxylation (RER)
- Hydroxylation of specific proline and lysine residues (requires vitamin C; deficiency →scurvy).
- Glycosylation (RER)
- Glycosylation of pro-α-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen α chains).
- Problems forming triple helix →osteogenesis imperfecta.
- Exocytosis of procollagen into extracellular space.
- Outside fibroblasts
- Proteolytic processing
- Cleavage of disulfide-rich terminal regions of procollagen, transforming it into insoluble tropocollagen.
- Reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by Cu2+-containing lysyl oxidase) to make collagen fibrils.
- Problems with cross-linking causes Ehlers-Danlos.
- Osteogenesis imperfect
- Genetic bone disorder (brittle bone disease ) caused by a variety of gene defects.
- Most common form is autosomal dominant with production of otherwise normal type I collagen.
- OI manifestations can include:
- Multiple fractures with minimal trauma; may occur during the birth process
- Blue sclerae due to the translucency of the connective tissue over the choroidal veins
- Hearing loss (abnormal ossicles)
- Dental imperfections due to lack of dentin
6 A teenager, new to your practice, comes in for a routine physical exam. His family had just moved to the city, and the boy had rarely seen a doctor before. Upon examination, you notice a high, arched palate, disproportionately long arms and fingers, a sunken chest, and mild scoliosis. The patient has been complaining of lack of breath while doing routine chores, and upon listening to his heart, you detect an aortic regurgitation murmur. Careful examination of the eye shows dislocated lens . Based on your physical exam and history, you are suspicious of an inborn error of metabolism in which of the following proteins?
6 The answer is B:
Fibrillin. The boy is showing the symptoms of Marfan syndrome, which is caused by mutations in fibrillin, an extracellular protein. Fibrillin helps to form, along with other proteins, microfi brils, which are present in elastic fibers (containing primarily elastin), which help to give various tissues their elastic properties. The exact mechanism whereby mutations in fibrillin lead to the symptoms of Marfan syndrome has yet to be established. Mutations in any of the other proteins listed do not give rise to Marfan’s (although collagen defects give rise to osteogenesis imperfecta, and dystrophin mutations give rise to various forms of muscular dystrophy, depending on the type of mutation). Marfan’s is an autosomal dominant disorder of connective tissue (not collagen). It is caused by mutations in the FBN1 gene (located on chromosome 15), which encodes fibrillin-1, a glycoprotein. The picture is of a dislocated lens, a classical finding in patients with Marfan’s.
7 A 8-year-old boy who appears to have a fracture in his arm. Upon taking a history, you learn that this child has been to the ER multiple times for fractures, and the incidents that lead to the fracture would be described as mild trauma at best. X-rays indicate a number of healed fractures that the boy and his parents were unaware of. Physical exam shows sky blue sclera. The parents then inform you that the child is taking bisphosphonates for his condition. The mechanism whereby the frequency of fractures is being reduced in this patient is which of the following?
(A) Increased synthesis of collagen
(B) Increased resorption of collagen
(C) Decreased synthesis of collagen
(D) Decreased resorption of collagen
(E) Increased synthesis of fibrillin
7 The answer is D:
Decreased resorption of collagen. The patient has a form of osteogenesis imperfecta, which is due to a mutation in collagen, generating brittle bones. Mild trauma is sufficient to break the bones. Bisphosphonates decrease bone resorption by the osteoclasts, thereby strengthening the bone, even with the defective collagen molecule. Bisphosphonates do not affect the synthesis of collagen or fibrillin.
A 14-year-old boy is brought to the pediatrician because of behavioral problems noted by the parents. Upon examination, the physician notices brittle and coarse hair, red patches on the skin, long, thin arms and legs , scoliosis, pectus excavatum, displaced lens, and muscular hypotonia. Blood work is likely to show an elevation of which of the following metabolites?
(D) Fibrillin fragments
10 The answer is E:
Homocystine. The boy is exhibiting the symptoms of homocystinuria, usually caused by a defect in cystathionine β-synthase. Cystathionine β-synthase will condense homocysteine with serine to form cystathionine. An inability to catalyze this reaction will lead to an accumulation of homocysteine, which will oxidize to form homocystine. The elevated serine can be metabolized back into the glycolytic pathway. Methionine will not increase in blood as the homocysteine produced is converted into homocystine. Phenylpyruvate is a diagnostic marker for PKU, but it is not relevant for homocysteine production or degradation. Fibrillin is mutated in Marfan syndrome, but this disorder is not Marfan syndrome.
31 .An example for derived amino acid seen in proteins:
- Hydroxy lysine
ANS: 31. C. Ornithine, citrulline are produced during the metabolism of amino acids. Beta-Alanine comes under the group of non a-amino acids. Only hydroxy lysine is the example for derived amino acids seen in proteins.lt is an important component of collagen.
64.Which amino acid is found usually in high amounts in collagen:
- Hydroxy leucine
- Hydroxy proline
ANS: 64. B. Collagen is the most abundant protein in mammals. If we see the sequence and composition of collagen fibers, every third amino acid residue is glycine. Proline and hydroxyl proline compose about 20 percent of collagen. The triple helix of collagen is stabilized by both non-covalent as well as covalent bonds. Proline residues as well as a smaller portion of lysine residues on the amino acid side of glycine residues are hydroxylated by prolyl or lysyl hydroxylase in the presence of the reducing agent ascorbic acid, this vitamin C deficiency reduces hydrogen bonding and weakness the collagen structure.
Pick out the incorrect statement:
- Histones are simple proteins
- Ceruloplasmin contain Zn as a metal ion
- Collagens, elastins and keratins are fibrous proteins
- Protamines resemble histones and are strongly basic in nature
ANS: 50. B. Ceruloplasmin contain Cu; carbonic anhydrase contain Zn as a metal ion. These are metallo proteins.
The following are the functions of ascorbic acid EXCEPT:
- Hydroxylation of tryptophan to serotonin
- In the synthesis of bile acids from cholesterol 7-a-hydroxylase enzyme requires vitamin C
- No role in maturation of RBC
- Helps in collagen synthesis
ANS: 52. C. Vitamin C helps in the maturation of RBC by reducing folic acid to tetrahydrofolate (THFA). Ascorbic acid along with folk acid helps in the maturation of RBC.
53 Scurvy is the deficiency manifestation of:
- Ascorbic acid
ANS: 53. A. Ascorbic acid deficiency produces a disease called scurvy, most symptoms are due to decrease in collagen synthesis leading to poor connective tissue formation and wound healing. Clinical features are swollen, sore, spongy gums with bleeding, loose teeth.
Which one of the following is not present in atherosclerotic plaque:
- Cholesterol and cholesterol esters
ANS: 37. C. Atherosclerosis is a complex disease characterized by thickening or hardening of arteries due to accumulation of plaque, this plaque contains cholesterol, cholesterol esters, collagen, proteoglycans and elastin. Calcium also can be deposited in advanced stage. The elasticity of blood vessel walls is decreased leading to an increase in blood pressure. Blood clots can form at plaques, this result in reduced flow of blood to vital organs, leading to ischemia and eventually heart attack or stroke. HDL (transport the cholesterol from extra hepatic tissues to liver) decreases the risk of atherosclerosis.
All of the following are post translational modifications EXCEPT:
- Proteolytic degradation
ANS: 53. C. Hydroxylation, carboxylation and proteolytic degradation are the post translational modifications. Hydroxylation occurs during the formation of collagen, the amino acids lysine and proline are converted to hydroxylysine and hydroxyproline by hydroxylation. Glutamic acid undergoes carboxylation in certain clotting factors. By proteolytic degradation some portions of precursor proteins are removed and active proteins are liberated.
Radiographic studies of a 65-year-old man with chronic hip pain reveal marked narrowing of the space between the femur and the hip socket. The patient is surgically treated with removal of the proximal femur and replacement with a prosthesis. Gross examination of the femoral head shows loss of much of the joint cartilage and multiple tiny clefts in the remaining cartilage. The disease process that produces this joint abnormality is thought to be related, in part, to proteolytic attack on which of the following types of collagen?
- Collagen type I
- Collagen type II
- Collagen type III
- Collagen type IV
- Collagen type V
it’s describing osteoarthritis and this is a process that affects articular cartilage (evidence in the vignette describing fibrillations etc), Ans is B : type II collagen.
An 18-year-old male takes an employment physical examination that is remarkable for a systolic murmur preceded by a distinct click on auscultation. The patient has unique body features, with unusually
long legs and long, tapering fingers. An ocular examination reveals
dislocation of the lens. An abnormality of which of the following
gene products is thought to underlie this condition?
- Myosin b-chain
The correct answer is D.
The genetic condition is Marfan syndrome, which is characterized by skeletal, ocular, and cardiovascular abnormalities. Typically, Marfan patients are tall with very long legs and tapering fingers. Laxity of joints is present, so that the thumb can be extended back to the wrist. Chest and spinal column deformities may be present as well. The most frequent cardiovascular anomalies are incompetence of the aortic valve, aortic dissection, and mitral valve prolapse (“floppy valve”). The latter may give rise to mitral regurgitation with the typical auscultatory phenomenon of a systolic click followed by a murmur. The most characteristic ocular change is ectopia lentis, i.e., dislocation of the lens. Most deaths are due to rupture of aortic dissections. The gene mutated in Marfan syndrome encodes fibrillin, a 350-kD protein that serves as scaffolding for the deposition of elastin and formation of elastic fibers. Elastin (choice C) is a 70-kD protein that constitutes the central core of elastic fibers. Abundant elastin is found in the walls of large arteries, uterus, skin, and ligaments. Although elastic fibers are disrupted by mutations of the fibrillin gene, the structure of elastin protein is intact in Marfan syndrome.
Collagen (choice A) is affected in a different set of genetic diseases, including Ehlers-Danlos syndromes and osteogenesis imperfecta.
Dystrophin (choice B) is a large transmembrane protein whose function is essential in maintaining the structural integrity of striated muscle fibers. Mutations of the dystrophin gene, located on X chromosome, are responsible for muscular dystrophy.
Mutations of the gene for myosin b-chain (choice E) account for more than one third of cases of hypertrophic cardiomyopathy, a condition characterized by hypertrophy of the left ventricle. Hypertrophic cardiomyopathy is not associated with mitral valve prolapse.
At which of the following sites is the characteristic triple helical
structure of the collagen initially formed?
- Extracellular space
- Golgi body
- Rough endoplasmic reticulum
- Smooth endoplasmic reticulum
The correct answer is B.
Collagen formation begins with transcription of mRNA from appropriate DNA genes in the nucleus. While still within the nucleus, the mRNA is spliced. It is then transported through the cytoplasm to the ribosomes on the rough endoplasmic reticulum. Individual chains are translated on the ribosomes, with the ends feeding into the endoplasmic reticulum lumen. Within the lumen, glycosylation of the individual chains occurs. The material then moves toward the Golgi bodies (whose lumens are connected to the endoplasmic reticulum) where the triple helices of procollagen form. The procollagen is then secreted into the extracellular space, where cleavage of pro-peptides and cross- linking of different triple helices occurs, maturing the collagen.
The extracellular space (choice A) is the site of procollagen cleavage and cross- linking.
The nucleus (choice C) is the site of mRNA transcription and splicing.
The rough endoplasmic reticulum (choice D) is the site of chain translation and glycosylation.
The smooth endoplasmic reticulum (choice E) does not participate in collagen synthesis
Type I collagen: (Identify 2 correct statements)
- contains two alpha1 chains and one alpha 2 chain
- is the most common collagen
- is the main type of collagen found in basement
- is found in skin and bone
- is found in cornea
Ans B, D are correct