11. Biochemistry | Protein Structure

What are the nonpolar, aliphatic amino acids?

Glycine, Alanine, Valine, Leucine, Isoleucine, Methionine, Proline

What are the key properties of nonpolar, aliphatic amino acids?

Hydrophobic; cluster in protein interiors

What are the nonpolar, aromatic amino acids?

Phenylalanine, Tryptophan

What are the key properties of nonpolar, aromatic amino acids?

Contain benzene-like rings

What are the polar, uncharged amino acids?

Serine, Threonine, Tyrosine, Cysteine, Asparagine, Glutamine

What are the key properties of polar, uncharged amino acids?

Hydrophilic; hydrogen bonding; -OH groups (Ser, Thr, Tyr) can be phosphorylated

What are the basic amino acids?

Lysine, Arginine, Histidine

What is the charge of basic amino acids at physiological pH?

Positively charged

What are the acidic amino acids?

Aspartic acid, Glutamic acid

What is the charge of acidic amino acids at physiological pH?

Negatively charged

What is the 21st amino acid?

Selenocysteine

Which amino acids contain hydroxyl groups and are phosphorylation sites?

Serine, Threonine, Tyrosine

Which amino acid contains a thiol group and forms disulfide bonds?

Cysteine

Which amino acid has an imidazole group with pKa ~6?

Histidine

Which amino acids have carboxylate groups and can bind calcium?

Aspartate, Glutamate

Which amino acid can be acetylated, methylated, or ubiquitinated?

Lysine

What is unique about Proline in secondary structure?

Rigid ring structure; breaks alpha helices

What is unique about Glycine in protein structure?

Smallest amino acid; increases flexibility; often found in bends

What is the definition of pKa?

pKa = - log Ka

What does a larger pKa indicate?

Weaker acid

What equation relates pH, pKa, and concentrations?

Henderson-Hasselbalch Equation: pH = pKa + log [A-]/[HA]

What is a zwitterion?

An amino acid form with no net charge at a specific pH (isoelectric point)

What are the detection methods for amino acids?

Ninhydrin test (purple color), chromatography, mass spectrometry

What is the primary structure of a protein?

Linear sequence of amino acids from N-terminus to C-terminus

What is the secondary structure of a protein?

Local folding via hydrogen bonds

What are common secondary structures?

Alpha-Helix, Beta-Sheets, bends, motifs

What disrupts alpha-helices?

Proline and Glycine

Where do bends occur in protein structure?

Near protein surface; susceptible to proteolysis

What a.a. induces bending in protein structure?

Proline

What is a motif?

Short sequence pattern (10-20 AA); e.g., C2H2 Zinc finger for DNA binding

What is the tertiary structure?

3D folding of a single polypeptide

What stabilizes tertiary structure?

Hydrogen bonds, disulfide bonds, hydrophobic interactions, electrostatics

What are domains in proteins?

Functional units (40-700 AA); may contain motifs; e.g., rhodopsin domain

What is a homologous domain?

Different proteins from different organisms performing similar fx

What is the quaternary structure of a protein?

Assembly of multiple polypeptides; e.g., hemoglobin

What is the native structure?

Properly folded, functional form of a protein

How does protein folding occur?

Can begin co-translationally; guided by primary structure and chaperones

What are chaperones?

Proteins (e.g., Hsp70, Hsp90) that assist in protein folding

What are conformational disorders?

Diseases caused by misfolded proteins; e.g., Alzheimer's‚ Parkinson's, Huntington's

What are amyloids?

Insoluble, misfolded protein aggregates; toxic and resistant to degradation

What are prions (PrP)?

Misfolded proteins that induce misfolding in other proteins

Which residues can be phosphorylated?

Serine, Threonine, Tyrosine

Which residues can be methylated?

Lysine, Arginine

Which residues can be acetylated?

Lysine, Arginine

Which residues can be hydroxylated?

Proline, Lysine

Which residue is targeted in ubiquitination?

Lysine

Which residues undergo glycosylation?

O-linked (Ser, Thr, Tyr), N-linked (Asn)

What is positive nitrogen balance?

Intake > loss; seen in pregnancy, growth, bodybuilding

What is negative nitrogen balance?

Loss > intake; caused by trauma, stress, anorexia, fasting

What is the recommended protein intake for healthy adults?

0.8g/kg/day of high-quality protein

What is the mnemonic for essential amino acids?

PVT TIM HALL

List the essential amino acids.

Phe, Val, Thr, Trp, Ile, Met, His, Arg, Leu, Lys

What are non-essential amino acids?

Synthesized from intermediates; e.g., Gly, Ala, Asp

What are conditionally essential amino acids?

Arg (children), Tyr (in PKU), Cys (needs Met for sulfur)

What causes Sickle Cell Anemia?

E6V mutation: Glutamate (polar, -) to Valine (nonpolar)

What is the clinical presentation of Sickle Cell Anemia?

Hemolytic anemia, pain crises, vaso-occlusion, organ damage

What causes Phenylketonuria (PKU)?

Conversion of Phe → Tyr - OH becomes defective → Tyr becomes essential

What is the clinical presentation of Phenylketonuria (PKU)?

Intellectual disability, seizures, musty odor, hypopigmentation

What causes Kwashiorkor?

↓ protein, normal calorie

What is the clinical presentation of Kwashiorkor?

Edema, hypoalbuminemia, fatty liver, stunted growth, anorexia

What causes Marasmus?

↓ calorie & ↓ protein

What is the clinical presentation of Marasmus?

Emaciation, muscle wasting, growth retardation, no edema

What causes Anorexia Nervosa?

Psychological eating disorder leading to extreme caloric restriction

What is the clinical presentation of Anorexia Nervosa?

Negative nitrogen balance, muscle breakdown, weight loss

What causes symptoms during starvation or fasting?

Muscle protein is broken down to support gluconeogenesis

What is the clinical consequence of starvation or fasting?

Loss of muscle mass, protein deficiency, fatigue

What causes Protein Conformational Disorders?

Misfolded proteins → toxic aggregates

What is the clinical presentation of Protein Conformational Disorders?

Neurological dysfunction; Alzheimer's, Parkinson's, Huntington's, Prion diseases

Where is the amino acid for a D-amino acid?

On the Rt

Where is the amino acid for an L-amino acid?

On the Lt

What is the relationship between D and L amino acids?

They are mirror images

Are D or L a.a. found in mammals?

L

When are amino groups positively charged?

In the protonated form

What is the form of the amino group when deprotonated?

Neutral

What is the protonated form of carboxylic groups?

Neutral

What is the deprotonated form of carboxylic groups?

Negatively charged

What is isoelectric point?

The pH at which the net charge on a molecule is zero

What is physiological pH?

7.4

What is pH of the stomach?

2–4

What is mass spectrometry?

Identifies a.a. based on molecular mass

What is the function of phosphorylation?

Alters enzymatic activity, protein interactions, signaling

What is the function of methylation?

Epigenetic regulation, transcription modulation

What is the function of acetylation?

Regulates gene expression, protein stability

What is the function of hydroxylation?

Required for collagen stability (e.g., hydroxyproline)

What is the function of ubiquitination?

Targets protein for degradation

What is the function of glycosylation?

Protein folding, stability, cell recognition

An adult comes into a primary care clinic to establish care. He states that he has a connective tissue disorder that does something to his blood vessels, which makes them prone to rupture. Assuming that this is a type of Ehlers-Danlos syndrome, what type of collagen is likely deficient?

A. Type 1 collagen
B. Type 2 collagen
C. Type 3 collagen
D. Type 4 collagen
E. Type 5 collagen

C

Type 1 collagen (A) defects cause osteogenesis imperfecta. Type 2 collagen (B) is involved in cartilage formation. Type 4 collagen (D) is not involved in the pathology of the vascular type of Ehlers-Danlos syndrome. Type 5 collagen (E) defects cause the skin hyperextension and joint hypermobility subtype of Ehlers-Danlos syndrome.

An 80-year-old man presented with impairment of higher intellectual function and alterations in mood and behavior. His family reported progressive disorientation and memory loss over the last six months. There is no family history of dementia. The patient was tentatively diagnosed with Alzheimer disease. Which one of the following best describes the disease?

A. It is associated with β-amyloid—an abnormal protein with an altered amino acid sequence.
B. It results from accumulation of denatured proteins that have random conformations.
C. It is associated with the accumulation of amyloid precursor protein.
D. It is associated with the deposition of neurotoxic amyloid peptide aggregates.
E. It is an environmentally produced disease not influenced by the genetics of the individual.

D

D. Alzheimer disease is pathologically characterized by the deposition of β-amyloid (Aβ) plaques and neurofibrillary tangles. The β-amyloid peptides, especially Aβ42, are neurotoxic aggregates formed from the cleavage of amyloid precursor protein (APP). These aggregates deposit extracellularly in the brain, contributing to neuronal dysfunction and neurodegeneration. This hallmark pathology underlies the cognitive decline and behavioral changes seen in Alzheimer disease.

A. It is associated with β-amyloid—an abnormal protein with an altered amino acid sequence.

Incorrect because β-amyloid in Alzheimer’s disease is not due to an altered amino acid sequence; it arises from abnormal processing (cleavage) of a normal protein, APP. The primary sequence of APP is normal in most sporadic Alzheimer cases.

B. It results from accumulation of denatured proteins that have random conformations.

Incorrect because while protein misfolding plays a role, the aggregates in Alzheimer’s are not random denatured proteins; they are structured amyloid fibrils formed by specific peptides like Aβ42 in a β-pleated sheet conformation.

C. It is associated with the accumulation of amyloid precursor protein.

Incorrect because it’s not the accumulation of APP itself that causes disease—it is the cleavage products, particularly Aβ42, that form plaques. APP is normally present in neurons and does not accumulate in Alzheimer’s.

E. It is an environmentally produced disease not influenced by the genetics of the individual.

Incorrect because although environmental factors may play a role, genetics is a significant factor. For example, mutations in APP, PSEN1, PSEN2, and the APOE ε4 allele are associated with familial and sporadic Alzheimer’s disease.