Clinical Correlates 2 Protein Structure

Question 1

Marfan syndrome results from mutations in the gene for the highly a-helical fibrillary protein ___, which is a major component of microfibrils found in the extracellular matrix. Patients have defective ____ tissue, particularly in the ligaments and aorta. They present with excessively long extremities and fingers, arachnodactyly, and a predisposition to dissecting aortic aneurysms and valvular disease.

Answer 1

fibrillin

connective

Question 2

Prion diseases like___ ___ result from the transmission of a proteinaceous agent that is capable of altering the normal a-helical arrangement of the prion protein and replacing it with b-pleated sheets and smaller a-helices, similar to the pathogenic form. The resulting misfolded protein is resistant to degradation, with death of the affected neurons. Patients suffer pronounced involuntary jerking movements (startle myoclonus) and rapidly deteriorating dementia.

Answer 2

Creutzfeldt-Jakob disease (CJD)

Question 3

The family of transcription factors known as homeobox proteins contains helix-turn-helix motifs. They play a significant role in pattern development during development of the limbs and other body parts. Disruption of protein–DNA interactions in these proteins may result in ____.

Answer 3

congenital malformations

Question 4

Heat shock proteins (hsps) are a group of chaperones. Mutations in such proteins sometimes lead to human disease. Some patients with ___ ___ disease, one of the most common inherited ___ diseases, have been found to have mutations in hsps.

Answer 4

Charcot-Marie-Tooth (CMT)

neuromuscular

Question 5

Mutations in patients with ____ deficiency result in a misfolded protein that gets trapped within the cell. Patients with decreased levels of this protease inhibitor manifest with ____ and emphysema.

Answer 5

a1-antitrypsin (AAT)

cirrhosis

Question 6

beta-amyloid

The most common cause of progressive dementia

Answer 6

Alzheimer disease

Question 7

beta2-microglobulin

Deposition of amyloid in bone joints results in arthritis and cartilage and bone destruction.

Answer 7

Hemodialysis-associated amyloidosis

Question 8

Calcitonin

Deposition of amyloid around the C cells of the thyroid, the source of the calcitonin

Answer 8

Medullary carcinoma of the thyroid

Question 9

immunoglobulin light chain

Patients have renal (myeloma kidney) and heart failure due to accumulation of protein in these tissues.

Answer 9

multiple myeoloma

Question 10

Islet amyloid protein

Deposition of the islet amyloid protein, normally secreted with insulin, may contribute to further islet dysfunction.

Answer 10

Type 2 diabetes mellitus

Question 11

Tranthyretin

Deposition of amyloid in neurons with axonal degeneration

Answer 11

Familial amyloidotic neuropathies

Question 12

____ ___ results from the expansion of a region of polyglutamine repeats within the ___ protein. The protein aggregates and forms intranuclear inclusions, resulting in neuronal cell death. Patients present with progressive movement disorders and dementia.

Answer 12

Huntington disease

Huntington

Question 13

The novel ___drug bortezomib (Velcade) is used for the treatment of multiple myeloma and inhibits the proteasome. It is believed that cancer cells are more dependent on proteasomal degradation than normal cells for proliferation, metastasis, and survival.

Answer 13

anticancer

Question 14

Proteins from the intracellular environment may be targeted for degradation by the ubiquitin–proteasomal pathway

Answer 14

The proteasome degrades proteins into small peptides, which are then further degraded into amino acid precursors or presented on the surface of cells as small peptides for immune recognition.

Question 15

Alternatively, some proteins are degraded in a PEST sequence–dependent manner.

Answer 15

Proteins that have PEST sequences in their N terminus (proline [P], glutamate [E], serine [S], and threonine [T]) are targeted for rapid degradation after synthesis by nonspecific proteases.

Question 16

Patients with _____syndrome have a defect in the ability to transfer enzymes from lysosomes to phagocytic vesicles. They have recurrent infections owing to a lack of microbial killing, anemia, and thrombocytopenia.

Answer 16

Chediak-Higashi

Question 17

In the mutant hemoglobin (HbS), a hydrophobic amino acid replaces an amino acid with a negative charge. This change allows deoxygenated molecules of HbS to polymerize. Red blood cells that contain large complexes of HbS molecules can assume a sickle shape. These cells undergo ___, and an anemia results. Painful vaso-occlusive crises also occur, and end-organ damage may result.

Answer 17

hemolysis

Question 18

Hemoglobin has about __ times the affinity for carbon monoxide than it does for oxygen. Prolonged or heavy exposure to carbon monoxide results in disorientation, headache, and potentially fatal asphyxiation. Patients may have ‘‘cherry-red mucous membranes’’ due to the accumulation of carboxyhemoglobin.

Answer 18

250

Question 19

Spectrin

Answer 19

Hereditary spherocytosis

Hereditary anemia and splenomegaly; treatment sometimes involves splenectomy.

Question 20

Dystrophin

Progressive motor weakness, eventual respiratory failure, and cardiac decompensation; X-linked inheritance.

Answer 20

Muscular dystrophy

Question 21

beta-myosin heavy chain

Answer 21

Familial hypertrophic cardiomyopathy
Enlargement of the heart with outlet obstruction. Most common cause of sudden, otherwise unexplainable death in young athletes.

Question 22

Collagen (alpha5 chain of Type IV collagen)

Answer 22

Alport syndrome

X-linked syndrome characterized by renal failure, nerve deafness, and cataracts.

Question 23

___ ___ is a group of related disorders in the synthesis of type I collagen. Such defects have a wide spectrum of clinical consequence, although they all share bone fragility (with a predisposition to multiple childhood fractures), hearing loss, and a distinctive blue sclera.

Answer 23

Osteogenesis imperfecta

Question 24

__ ___ is a group of disorders characterized by a defect in the synthesis or structure of collagen. One of the subtypes, ___ ___, results from a defect in the enzyme lysyl hydroxylase. Defects in collagen synthesis are characterized by hyperextensible skin, laxity of joints, and defects in large blood vessels.

Answer 24

Ehlers-Danlos syndrome

Ehlers-Danlos type VI

Question 25

Synthesis of insulin a. Preproinsulin, consisting of the A and B chains joined by a C-peptide, is synthesized on the rough endoplasmic reticulum and the pre- (signal) sequence is removed to form proinsulin.

Answer 25

b. In secretory granules, proinsulin is cleaved, and the C-peptide is released. The remainder of the molecule forms the active hormone.

Question 26

C-peptide levels are used to differentiate the causes of high insulin in patients. In cases of low blood glucose due to increased levels of circulating insulin via __ ___, as in tumors of pancreatic b cells, serum levels of C-peptide will also be elevated. However, in cases of surreptitious insulin administration (purposeful injection of insulin), C-peptide is not elevated because commercial insulin preparations have purified away this ___

Answer 26

endogenous production | contaminate.

Question 27

1. Which of the following statements is correct concerning prion disease? (A) It is a disease process in which proteins appear to be the sole pathophysiologic entity (B) It is a disease process in which a messenger RNA secondary structure appears to be the sole pathophysiologic entity (C) The disease is only found in humans (D) Effective treatments are available for the disease (E) The disease process is readily reversible

Answer 27

A. Prion diseases include a handful of diseases that affect animals (e.g., bovine spongiform encephalopathy is ‘‘mad cow disease’’) and humans (Creutzfeldt-Jakob disease). The pathogenesis is mediated primarily by a protein that can exist in two conformations: one normal, the other leading to disease. The abnormally folded proteins are resistant to degradation by the host and affect the central nervous system. The change in protein structure is not reversible. The messenger RNA in the disease state is not altered compared with the normal state. There is no effective treatment, and patients develop rapidly progressive dementia.

Question 28

``` 2. The mutation associated with Marfan syndrome is with the fibrillary protein fibrillin. What aspect of protein structure is affected in this disorder? (A) b-turn (B) b-sheet (C) Primary structure (D) Tertiary structure (E) Quaternary structure ```

Answer 28

C. The fibrillin mutation found in Marfan syndrome results in a defective a-helix due to an alteration in the sequence of amino acids in the protein, an altered primary structure. The tertiary and quaternary structures are not altered, nor are b-sheets or turns. Additionally, it is important to note that the main organ systems affected are the musculoskeletal system (arachnodactyly, dolichostenomelia, scoliosis), cardiovascular system (acute aortic dissection, mitral valve prolapse), pulmonary system (spontaneous pneumothorax), and eyes (lens subluxation, decreased nighttime vision).

Question 29

``` 3. A 65-year-old man with a history of type 2 diabetes is complaining of blurred vision and numbness in his toes. Laboratory results were significant for increased blood urea nitrogen (BUN) and creatinine, indicative of renal failure. Laboratory work also revealed an HbA1C of 9.0. One of the mechanisms for the damage responsible for the man’s symptoms is the nonenzymatic covalent bonds formed between glucose and structural proteins. How would this reaction best be classified? (A) Acylation (B) Carboxylation (C) Glycation (D) Hydroxylation (E) Esterification ```

Answer 29

C. Glycation refers to the reaction of the aldehyde group of glucose reacting with the amino groups of protein, forming an amide linkage. The increased rate of glycation of collagen during hyperglycemia is implicated in the development of complications of diabetes, such as blindness and renal and vascular disease. Clotting factors are often carboxylated; histones can be acylated. Collagen is a prominent example of a protein that is hydroxylated during its production.

Question 30

4. A 24-year-old man presents to your clinic with several concerning symptoms. He states that he has uncontrollable movements called chorea, occasional stiffness, slurring of speech, difficulty planning his day and balancing his checkbook, and bouts of anxiety and crying spells. He also professes that this has been noted in some relatives on his mother’s side. What is true about the nature of the molecular mutation of this disorder? (A) A point mutation in a single gene (B) A nucleotide deletion in a single gene (C) A triplet repeat expansion within a gene (D) A frameshift mutation within a gene, creating a truncated protein (E) A chromosomal deletion of many bases that covers many genes

Answer 30

C. This patient has all the classic signs and symptoms of Huntington disease. Huntington disease is an autosomal dominant disorder that involves the huntington gene. This gene encodes a sequence of repeating trinucleotides, which gives rise to a polyglutamine stretch in the protein. In certain individuals, those that express Huntington disease, this trinucleotide repeat is greatly expanded, and the stretch of polyglutamine in the protein is enlarged, leading to a dysfunctional protein that, over time, leads to altered neuronal function. Other diseases that result from trinucleotide repeat expansion include spinobulbar muscular atrophy, spinocerebellar ataxia, fragile X syndrome, Friedreich ataxia, and myotonic dystrophy. Huntington disease is not due to a single nucleotide change, a frameshift mutation, or a deletion event within the gene.

Question 31

5. A 2-week-old infant presents to your rural family medicine clinic and appears ill; he is febrile and jaundiced and has extensive, reddened skin. According to his mother, it appears that since the delivery of the baby at home he has always ‘‘carried a fever.’’ You are able to send off some laboratory tests and are surprised to see that he has significant neutropenia and hypergammaglobulinemia. What is the most likely diagnosis? (A) DiGeorge syndrome (B) Severe combined immunodeficiency disease (C) Chediak-Higashi syndrome (D) Wiskott-Aldrich syndrome (E) Myeloperoxidase deficiency

Answer 31

C. This patient has Chediak-Higashi syndrome, a primary immunodeficiency disorder of phagocytic vesicles in which the lysosomes are unable to destroy bacteria. Primary immunodeficiency disorders are grouped into humoral/antibody/B-cell disorders (e.g., hypogammaglobulinemia, common variable immunodeficiency, leukocyte adhesion deficiency), cellmediated/T-cell disorders (e.g., DiGeorge syndrome), combined humoral and cell-mediated deficiencies (e.g., severe combined immunodeficiency, Wiskott-Aldrich syndrome), complement deficiencies (e.g., angioedema), and phagocyte dysfunction (e.g., Chediak-Higashi syndrome). All these disorders affect children early in life and are associated with significant morbidity and mortality.

Question 32

7. A 27-year-old firefighter is brought to the emergency room after being exposed to smoke during a training exercise. He looks ill and has labored breathing. He is clutching his head and exhibits an altered mental status. On examination, you note that he appears red, and his pulse oximetry reads 100%. You suspect carbon monoxide toxicity. What is true of the oxygen saturation curve during carbon monoxide toxicity? A) The oxygen saturation curve is shifted to the left. (B) The oxygen saturation curve is shifted to the right. (C) The effect of carbon monoxide on hemoglobin is similar to that of having increased levels of 2,3 bisphosphoglycerate. (D) The effect of carbon monoxide on hemoglobin is similar to that of a low pH state. (E) The effect of carbon monoxide on hemoglobin is similar to that of an increased temperature state.

Answer 32

A This shifts the oxygen binding curve to the left. Because the oxygen now has a higher affinity for hemoglobin, it is more difficult for hemoglobin to release oxygen to the tissues, leading to hypoxia despite oxygen being bound to hemoglobin. Conditions that shift the curve to the right allow oxygen to be released more readily: low pH, increased PCO2, increased temperature, presence of 2,3-bisphosphoglycerate, and absence of carbon monoxide.

Question 33

``` 8. A 59-year-old man presents with nephrotic syndrome. Immunoelectrophoresis detects a monoclonal immunoglobulin G (IgG) l subtype in his serum and free l light chains in his urine. A renal biopsy shows amyloidosis. Although several different proteins are precursors to amyloid deposition, all amyloid fibrils share an identical secondary structure that is which of the following? (A) a-Helix (B) b-Pleated sheet (C) Triple helix (D) Helix-turn-helix (E) Leucine zipper ```

Answer 33

B. Regardless of the type of amyloid disease, the pathogenesis is related to the accumulation of b-pleated protein. In the case of multiple myeloma, it is the accumulation of immunoglobulin light chains in the kidney and heart. a-Helical proteins include native fibrillary proteins. The triple helix is a unique structure found in collagen. Helix-turn-helix and leucine zippers are supersecondary structures that are often found in transcription factors, like homeobox proteins (helix-turn-helix).

Question 34

``` 9. The patient described in question 8, who has multiple myeloma, has not responded to numerous treatments, and his disease is progressing. He sees his oncologist, who wants to start him on the drug bortezomib. Bortezomib inhibits the proteasome from degrading proteins. Which class of intracellular proteins will not be specifically degraded as a result of taking this drug? (A) Proteins with PEST sequences (B) Amyloid proteins (C) Polyubiquitinated proteins (D) Immunoglobulin light chains (E) Immunoglobulin heavy chains ```

Answer 34

C. The proteasome normally degrades proteins that have been polyubiquitinated. As such, in the presence of bortezomib, polyubiquitinlated proteins will accumulate within cells, leading to a selective adverse effect on the cancer cells (myeloma cells) because these are the cells growing most rapidly. Proteins with PEST sequences are rapidly degraded by nonspecific intracellular proteases. Although the immunoglobulin light chains are forming the amyloid proteins in this disease, these structures are difficult to degrade, such that inhibiting the proteasome has no effect on the degradation of the amyloid proteins. Immunoglobulin heavy chains are not accumulating in this disorder.