Lecture_5_notes_Protein_Structure_BCH400_Spring_2025_v2

Chapter 4: Protein Structure and Function

Key Functions of Proteins

Catalysis

Proteins act as enzymes that catalyze biochemical reactions in living organisms.

• Enolase: An enzyme critical for the glycolytic pathway, facilitating the conversion of glucose to pyruvate for energy production.

• DNA Polymerase: Essential for DNA replication, it synthesizes new DNA strands from nucleotides, ensuring genetic material is accurately copied during cell division.

Communication

Proteins play vital roles in cellular communication.

• Cell Surface Receptors: These proteins bind to signaling molecules like hormones or neurotransmitters, triggering a cellular response.

• Antibodies: Immune system proteins that identify and neutralize foreign objects like bacteria and viruses.

• Peptide Hormones (e.g., oxytocin and vasopressin): These are signaling molecules that regulate various physiological processes such as labor contractions and water balance in kidneys.

• Toxins: Proteins that can disrupt biological processes or cellular functions, often used as defense mechanisms by organisms.

Transport

Proteins are crucial for the transport of molecules across membranes and within organisms.

• Hemoglobin: A respiratory protein that binds oxygen in the lungs and transports it to tissues for cellular respiration.

• Lactose Permease: A membrane protein that facilitates the transport of lactose across cell membranes, essential for energy metabolism in some organisms.

Motion

Proteins are responsible for movement at various levels, from cellular motility to muscle contraction.

• Myosin: A motor protein that interacts with actin for muscle contraction and movement of cellular components.

• Actin: Plays roles in cell motility and structural integrity by forming the cytoskeleton that supports cell shape and movement.

Structure

Proteins provide structural support to cells and tissues.

• Collagen: A major component of connective tissues, providing strength and structural support in tissues such as skin, tendons, and cartilage.

• Keratin: Fibrous proteins in hair, nails, feathers, and horns that play critical structural and protective roles.

• Cytoskeleton Components: Actin and tubulin are integral parts of the cell's cytoskeleton, providing shape, support, and transport pathways within cells.

Importance of Size and Functional Roles

Small Peptide Hormones

• Vasopressin: This peptide hormone is crucial for regulating blood pressure by promoting water reabsorption in the kidneys.

• Oxytocin: Known for its role in childbirth and lactation, it stabilizes physiological processes and emotional bonding among individuals. A precursor to oxytocin undergoes enzymatic processing by peptidylglycine alpha-amidating monooxygenase (PAM), which is activated by vitamin C.

Disulfide Bonds and Protein Modifications

• Ozempic: A modified glucagon-like peptide that is used in the management of type II diabetes and aids in weight loss by mimicking the effects of incretin hormones.

Ricin: A Potent Toxin

Toxicity and Mechanism

• Lethal Dose: As little as 8 beans (500 micrograms) of ricin can lead to fatal outcomes. This compound has been historically weaponized (e.g., by the KGB).

• Mechanism:

  • Ricin A subunit: Acts as an N-glycoside hydrolase that depurinates adenine in ribosomal RNA, leading to the cessation of protein synthesis.

  • Ricin B subunit: Facilitates the entry of the toxin into the cells, enhancing its toxicity.

• Toxicity Comparison: Ricin is deemed to be 6000 times more toxic than cyanide and 12000 times more than the venom of a rattlesnake, highlighting its extreme lethality.

Peptide Bonds

• Formation: Peptide bonds arise from a condensation reaction, where two amino acids join together while losing a water molecule.

• Characteristics: The partial double-bond character of the peptide bond restricts rotation around it, resulting in a bond that is rigid and nearly planar, which has profound implications for the protein’s geometry.

• The bond angles involved in the structure are represented as phi (φ) and psi (ψ), which are critical in understanding protein folding and function.

Secondary Structure

General Overview

• Secondary Structure: Refers to the local folded structures that form within a protein due to hydrogen bonding between amino acid residues.

  • Alpha Helix: Stabilized by hydrogen bonds between the backbone atoms of the polypeptide chain, resulting in a right-handed helix with approximately 3.6 amino acids per turn.

  • Beta Sheet: Formed from hydrogen bonds between adjacent strands of the polypeptide chain, which can be organized in parallel (strands running in the same direction) or antiparallel (strands running in opposite directions).

Ramachandran Plot

• Significance: A crucial tool used for visualizing the allowed conformations of amino acids in proteins, it plots the possible angles of φ and ψ, aiding in the prediction of protein structure based on these backbone torsional angles.

Tertiary Structure of Proteins

Characteristics and Stability

• Tertiary Structure: The overall three-dimensional shape of a protein, crucially determined and stabilized by various interactions:

  • Hydrophobic Effects: Nonpolar side chains tend to avoid water and aggregate in the protein's core, driving the folding process.

  • Hydrogen Bonds: Form between polar side chains to stabilize the structure.

  • Van der Waals Interactions: Transient attractions between uncharged atoms contribute to protein stability.

  • Electrostatic Interactions: Attractive forces between charged side chains can also stabilize protein structure.

  • Cystine Bridges (disulfide bonds): Covalent bonds between cysteine residues contribute significantly to the overall stability of the protein.

Protein Folding and Denaturation

• Denaturation: The process by which proteins lose their three-dimensional structure, leading to loss of function, often induced by environmental stressors like heat, extreme pH, and certain chemicals.

• Ribonuclease Example: This enzyme fully denatures in the presence of urea and beta-mercaptoethanol, but interestingly, it can refold to regain its enzymatic activity under favorable conditions.

Quaternary Structure

• Example: Hemoglobin: Comprises two alpha and two beta chains, showcasing functional quaternary structure achieved through the assembly of polypeptide subunits into a larger, active complex.

• Protein Folding: The folding process follows hierarchical stages where smaller secondary structure regions first assemble to reduce alternative conformations. Chaperones play a significant role in preventing misfolding and assisting in the proper folding of proteins.

Disease from Protein Misfolding

• The misfolding of proteins can lead to the propagation of further misfolding and aggregation, resulting in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

• Amyloid-beta Fibrillation in Alzheimer's: This process involves the cleavage of amyloid precursor proteins (APP) by secretases, producing peptide fragments that aggregate, leading to synaptic dysfunction and subsequent neuronal damage.