Lecture 5

Introduction to Proteins

Proteins are one of the four major classes of biological molecules essential for all forms of life. They are composed of amino acids linked by peptide bonds and perform a vast array of functions necessary for the growth, repair, and maintenance of cells and tissues. Their diverse roles and complex structures make them indispensable for various biological processes and functions.

Review of Protein Functions

• Catalysis: Enzymes, which are specialized proteins, act as catalysts in biochemical reactions. They lower the activation energy needed for reactions to proceed, allowing them to occur rapidly and efficiently, which is crucial to sustaining life.

  • Example: Telomerase, discovered by Carol Greider, is essential for cellular longevity by maintaining the ends of chromosomes, known as telomeres, preventing chromosomal deterioration during cell division.

• Transport: Many proteins serve vital roles in transporting substances within organisms.

  • Hemoglobin: A globular protein that carries oxygen in the bloodstream, facilitating gas exchange in tissues.

  • Lipoproteins: These proteins transport fats in the bloodstream, playing a critical role in lipid metabolism.

• Storage: Proteins are used for storing nutrients, which are essential for energy and cellular functions.

  • Example: Ferritin stores iron in a form that is usable by the body when needed, while casein in milk serves as a protein reservoir for developing offspring.

• Movement: Proteins are a fundamental component of muscle contraction and movement in both single-celled and multicellular organisms.

  • Example: The actin-myosin system is pivotal for muscle contraction, allowing for movement and locomotion.

• Structural Role: Proteins serve as key structural components of cells and tissues, providing shape and support.

  • Example: Collagen, a fibrous protein, forms the extracellular matrix in connective tissues, contributing to skin, bone, and cartilage integrity.

• Defense: The immune system employs proteins, particularly antibodies, to fight against pathogens such as bacteria and viruses, providing a critical defense mechanism for maintaining health.

• Regulation and Hormones: Many hormones, which are signaling molecules, are proteins that help regulate physiological processes, including metabolism, growth, and reproduction.

  • Example: Insulin is a peptide hormone that regulates blood glucose levels.

• Miscellaneous Functions: Some proteins have unique roles tailored to specific environmental challenges.

  • Example: Antifreeze proteins found in Arctic fish prevent ice crystal formation, while sweetness proteins in fruits attract pollinators and aid in seed dispersal.

Protein Structure

Proteins fold into complex three-dimensional shapes essential for their function. The specific three-dimensional conformation directly correlates with their biological function.

Levels of Protein Structure

1. Primary Structure:

   • The linear sequence of amino acids linked by peptide bonds, which determines the protein's unique characteristics.

2. Secondary Structure:

   • Local three-dimensional arrangements of the polypeptide chain, primarily alpha helices and beta sheets, stabilized by hydrogen bonds.

   • Alpha Helix: A coiled structure formed by hydrogen bonding between amino acids spaced apart in the sequence, contributing to the protein's stability.

   • Beta Sheet: Formed through hydrogen bonding between different sections of a polypeptide, which can be located far apart in the primary sequence.

3. Tertiary Structure:

   • The overall three-dimensional shape of a polypeptide chain due to interactions among secondary structures, including hydrophobic interactions, ionic bonds, and hydrogen bonds, which define the spatial arrangement of all atoms in the protein.

4. Quaternary Structure:

   • Formed by the assembly of multiple polypeptide chains, creating a functional protein.

   • Example: Hemoglobin consists of four polypeptide chains and is responsible for oxygen transport in the blood.

Secondary Structure Details

• Hydrogen Bonds: These bonds play a critical role in stabilizing structures like alpha helices and beta sheets, which are crucial for maintaining protein integrity.

• Structural Variations:

  • Amphiphilic Alpha Helices: These contain both hydrophilic (water-attracting) and hydrophobic (water-repelling) regions, allowing them to integrate into cell membranes effectively.

  • Beta-Pleated Sheets: Can exist in parallel or antiparallel arrangements, with antiparallel structures being notably more stable due to the linear alignment of hydrogen bonds.

Specific Protein Types

• Fibrous Proteins: Typically consist of one dominant type of secondary structure and provide support, shape, and strength.

  • Example: Keratin in hair and nails, and collagen in connective tissues.

• Globular Proteins: Contain multiple types of secondary structures, are generally water-soluble, and perform various functional roles.

  • Example: Serum albumin, highly abundant in blood plasma, plays a role in osmotic pressure and carries various substances.

Protein Folding Mechanism

Proteins do not fold through random motion; instead, they undergo a specific stepwise process, forming secondary structures first, followed by tertiary structures. The unique sequence of amino acids in the primary structure ultimately dictates the final folded structure and thus, its function.

Experimental Analysis of Protein Folding

The Anfinsen Experiment illustrated that the primary structure of ribonuclease determines its three-dimensional shape and functionality. Denaturation can lead to unfolding; however, upon removal of denaturing agents, the protein can spontaneously refold, demonstrating that correct folding is often thermodynamically favorable.

Chaperones and Non-spontaneous Folding

Certain complex proteins require assistance from chaperones—specialized proteins that facilitate proper folding and prevent misfolding, particularly in proteins like RuBisCO, which plays a crucial role in photosynthesis.

Stability Factors in Protein Structure

• Hydrophobic Interactions: Serve as a major driving force for protein folding by minimizing the exposure of hydrophobic residues to the aqueous environment.

• Electrostatic Interactions: Ionic bonds between charged side chains offer stabilization, contributing significantly to protein structure.

• Hydrogen Bonds: Stabilizing elements in alpha helices and beta sheets, which are critical for maintaining protein integrity.

• Disulfide Bonds: Covalent links formed between cysteine residues provide further stabilization and contribute to the structural integrity of proteins.

Protein Misfolding Diseases

Misfolded proteins can lead to severe diseases, including:

• Prion Diseases: Result from the heritability of misfolded protein states, leading to neurodegeneration (e.g., Creutzfeldt-Jakob Disease).

• Alzheimer's Disease: Characterized by the aggregation of misfolded proteins, leading to cellular dysfunction.

• Parkinson's Disease: Associated with the accumulation of misfolded alpha-synuclein protein.

• Sickle Cell Disease: Results from a single amino acid substitution that leads to misfolding and aggregation of hemoglobin, causing severe health complications.

AI and Protein Structure Prediction

The emergence of AI tools, such as AlphaFold, has revolutionized the prediction of protein structures directly from amino acid sequences, achieving over 90% accuracy. This groundbreaking technology enables researchers to understand protein functions better and has the potential to engineer new proteins tailored for specific therapeutic applications

Conclusion for Future Studies

A deeper understanding of protein folding mechanisms and structures is essential for advancing biological research, developing new therapies, and addressing protein misfolding diseases, highlighting the crucial role proteins play in health and disease.