Ch5 Prep: Key Concepts in Protein Structure

Review of Foundational Principles

• Noncovalent forces such as hydrogen bonds, ionic interactions, and van der Waals forces are essential for the structure and function of biological molecules.

• Protein structure is described at four levels: primary, secondary, tertiary, and quaternary.

• Some proteins can adopt multiple conformations, contributing to their functional diversity.

• Proteins with more than one polypeptide chain exhibit quaternary structure.

Ch5 Learning Objectives: Protein Structure

• Compare the structures and functions of myoglobin and hemoglobin.

• Relate genetic variations to changes in protein function.

• Compare the structures and functions of structural proteins.

• Explain how motor proteins operate.

Myoglobin and Hemoglobin: Oxygen-Binding Proteins

Structures and Functions

• Myoglobin is a classical globular protein that stores oxygen in muscle tissue.

• Hemoglobin is a tetrameric protein in red blood cells responsible for oxygen transport from lungs to tissues.

• Both proteins contain a heme prosthetic group that binds oxygen via an iron (Fe) atom.

Heme Prosthetic Group

• Heme is a porphyrin ring that chelates Fe2+ for oxygen binding.

• Definition: A prosthetic group is an organic molecule tightly bound to a protein, essential for its function.

Oxygen Binding Mechanism

• Oxygen binding to myoglobin depends on oxygen concentration and is reversible.

• The central Fe(II) atom in heme coordinates with four porphyrin nitrogens and one histidine residue below the plane; O2 binds at the sixth coordination site.

Oxygen Binding Curves

• Myoglobin binds O2 in a hyperbolic trend:

• Hemoglobin binds O2 cooperatively, resulting in a sigmoidal curve:

Sigmoidal binding reflects allosteric interactions between subunits.

Structural Comparison

• Myoglobin and hemoglobin share similar secondary and tertiary structures but differ in quaternary structure (hemoglobin is a tetramer; myoglobin is monomeric).

• Primary sequence identity is ~18%, but structural similarities indicate a common evolutionary origin.

Cooperative Binding and Conformational Change

• Hemoglobin undergoes conformational changes upon O2 binding, shifting from a tense (T) to relaxed (R) state.

• This transition underlies cooperative oxygen binding, enhancing O2 delivery to tissues.

Bohr Effect and BPG Regulation

• The Bohr effect: As pH increases, hemoglobin's affinity for O2 increases.

• In tissues, metabolic CO2 production lowers pH, promoting O2 release.

• 2,3-Bisphosphoglycerate (BPG) binds to deoxyhemoglobin, stabilizing the T state and decreasing O2 affinity.

Summary Table: Myoglobin vs. Hemoglobin

Hemoglobin Variants and Genetic Disorders

Inherited Disorders

• Over 1200 hemoglobin variants exist, many due to mutations in α or β globin genes.

• Sickle cell hemoglobin (Hb S): E6V mutation in β chain (Glu → Val) causes sickling of red blood cells, leading to anemia and other complications.

• Carriers (heterozygotes) of Hb S have increased resistance to Plasmodium falciparum malaria.

• Hemoglobin C: E6K mutation in β chain, also confers malaria resistance, associated with mild anemia.

• Thalassemias: Genetic defects reducing synthesis of α or β chains, common in Mediterranean and South Asian populations; symptoms range from mild anemia to severe disease.

Summary Table: Hemoglobin Variants

Structural Proteins

Cytoskeletal Filaments

• Actin filaments (microfilaments): Polymers of globular actin, most abundant in cells, involved in cell shape and movement.

• Microtubules: Hollow fibers built from α and β tubulin dimers, essential for cell division, intracellular transport, and structural integrity.

• Intermediate filaments: Provide mechanical strength, composed of proteins like keratin and vimentin.

Assembly and Dynamics

• Actin filaments grow by addition of subunits at both ends, with the (+) end growing faster.

• Treadmilling: Rate of addition at one end matches removal at the other, maintaining constant filament length.

• Microtubules are formed by lateral association of protofilaments, typically 13 per tube.

Collagen Structure

• Collagen: Major extracellular structural protein, forms a triple helix with unique amino acid composition (every third residue is glycine; high proline and hydroxyproline content).

• Collagen fibers are stabilized by covalent cross-links formed after synthesis.

Summary Table: Structural Proteins

Motor Proteins

Mechanisms of Action

• Myosin: Motor protein with two heads and a long tail, binds actin and ATP; ATP hydrolysis drives movement along actin filaments.

• Kinesin: Microtubule-associated motor protein, moves cargo processively toward the (+) end of microtubules using ATP hydrolysis.

Reaction Cycles

• Myosin: Binds ATP, hydrolyzes it, and undergoes conformational changes to 'walk' along actin filaments.

• Kinesin: Alternates binding and release of ATP and microtubule, resulting in stepwise movement of cargo.

Comparison Table: Myosin vs. Kinesin

Review Questions

• Explain how homologous protein sequences reveal essential residues.

• Sketch and interpret oxygen-binding curves for myoglobin and hemoglobin.

• Describe the molecular basis of cooperative binding in hemoglobin.

• Discuss the physiological effects of hemoglobin variants and structural protein mutations.

• List cellular activities requiring motor proteins and explain their reaction cycles.

Additional info: Hyperbolic and sigmoidal binding curves are fundamental in biochemistry for understanding ligand-protein interactions. The Bohr effect and BPG regulation are critical for physiological adaptation to varying oxygen demands. Structural proteins and motor proteins are essential for cellular architecture and dynamics.