Protein Secondary Structures and Protein Types 9-22

Secondary Structures of Proteins

• Beta Sheets:

  • Characterized by an N-to-C orientation. The backbone consists of alternating $NH$, $C_{\alpha}$, $CO$ groups.

  • Stabilized by hydrogen bonds: The carbonyl group ($CO$) from one beta strand forms a hydrogen bond with the $NH$ group on an adjacent beta strand, and this alternates along the structure.

  • Connections between beta strands:

    • If the beta sheet is long, it is usually connected by an alpha helix (N-to-C orientation continues along the alpha helix).

    • If the beta sheet is short, a beta bend (or beta turn) is sufficient for connection.

• Beta Turns (Beta Bends):

  • Allow polypeptide chains to reverse direction abruptly.

  • Stabilized by a single hydrogen bond across four amino acids.

  • Two main types: Type 1 and Type 2.

  • Amino Acid Composition: Often involve specific amino acids like Glycine (Gly) and Proline (Pro).

    • Type 1: Glycine, Proline, X, X

    • Type 2: X, Proline, Glycine, X (where X is any amino acid)

  • The difference between Type 1 and Type 2 relates to the specific conformation and the position of the proline residue.

Membrane Proteins

• Primary Structure: Consists of alternating stretches of hydrophilic and hydrophobic amino acids.

  • The N-terminal and C-terminal regions are typically hydrophilic, interacting with the aqueous environment.

  • Internal stretches of amino acids are hydrophobic.

• Embedding in Cell Membrane: These proteins are embedded within the lipid bilayer.

  • Hydrophilic regions face the aqueous environments (cytoplasm and extracellular space).

  • Hydrophobic regions interact with the lipid tails within the membrane.

• Transmembrane Segments (TMS):

  • Hydrophobic stretches that span the lipid bilayer.

  • Often adopt secondary structures allowing them to traverse the membrane effectively, such as the $4.4_{16}$ helix (pi helix) or other helices that provide a wider structure to cover longer distances within the membrane.

    • Other common helices for context (though not specifically for TMS coverage): $3.0<em>{10}$ helix (shorter), $3.6</em>{13}$ helix (alpha helix, intermediate).

  • Calculation of TMS length: The distance between two amino acids along a helix axis is approximately $0.15$ nanometers ($0.15$ nm).

    • Length of TMS = (Number of amino acids in TMS) $\times 0.15 \text{ nm}$.

    • Example: For $20$ amino acids in a TMS, the length would be $20 \times 0.15 \text{ nm} = 3.0 \text{ nm}$.

• Functions: Act as tunnels, channels, or transporters, facilitating the movement of substances across the cell membrane.

Fibrous Proteins

• Primarily serve structural roles within organisms.

Alpha-Keratin

• Location: Found in nails, claws, animal horns, skin, and hair.

• Types: Alpha-keratin exists in Type 1 and Type 2 forms, often differing in their amino acid sequences and arrangements.

• Sequence Motif: Contains a repeating a-b-c-d-e-f-g pattern along a rod domain ($310-314$ amino acids long).

  • Amino acids at positions a and d are predominantly hydrophobic, contributing to the protein's relative insolubility in water.

• Insolubility: Enhanced by:

  • The presence of hydrophobic amino acids.

  • Disulfide linkages (sulfur-sulfur bonds) between cysteine residues.

• Hierarchical Stacking: Alpha-keratin exhibits a complex hierarchical structure:

  1. Individual right-handed alpha helices.

  2. Two right-handed alpha helices twist together to form a left-handed coiled-coil dimer.

  3. Two such left-handed coiled-coil dimers associate in a right-handed twist to form a tetramer (protofilament).

  4. Protofilaments further assemble into larger bundles (e.g., $16$ helices) which contribute to the macroscopic structure of hair, nails, etc.

• Properties: Provides both strength and flexibility.

• Other Examples: Similar coiled-coil structures are found in materials like spider webs and cocoons.

Collagen

• The most abundant protein in mammals, known for its triple helix structure.

• Location: Found extensively in bones, teeth, skin, cartilage, blood vessels, tendons, and ligaments.

• Types: There are multiple types of collagen, each with specific locations and structural variations:

  • Type 1: Comprises two identical alpha helices and a third slightly different helix, forming a triple helix. Found in bones, teeth, and skin.

  • Type 2: Consists of three identical alpha helices forming a triple helix. Predominantly found in cartilage.

  • Type 3: Also composed of three identical alpha helices. Found in blood vessels.

• Length: Collagen polypeptides are very long, typically about $1000$ amino acids.

• Sequence Motif: A distinctive feature is the repeating sequence Gly-X-Y, where Glycine (Gly) appears every third amino acid.

• Post-Translational Modifications: After the collagen triple helix is formed, several crucial modifications occur:

  1. Proline Hydroxylation: Proline residues are modified to 3-hydroxyproline or 4-hydroxyproline.

     • Catalyzed by prolyl hydroxylase.

  2. Lysine Hydroxylation: Lysine residues are converted to 5-hydroxylysine.

     • Catalyzed by lysyl hydroxylase.

  • Both hydroxylase enzymes require Vitamin C (ascorbate) and alpha-ketoglutarate as cofactors.

• Clinical and Physiological Implications:

  • Aging: As individuals age, lysine residues in collagen can undergo glycosylation (binding to sugars like galactose and glucose). This cross-linking leads to increased stiffness in tissues.

    • Consequences: Contributes to arthritis, stiffening of blood vessels (leading to high blood pressure, stroke, and heart disease).

  • Vitamin C Deficiency (Scurvy): Lack of Vitamin C impairs the activity of prolyl and lysyl hydroxylases. Without proper hydroxylation, collagen cannot form stable triple helices and cross-links.

    • Manifestations: Weak blood vessels, skin lesions, gum disease, and impaired wound healing. Historically observed in sailors on long voyages without fresh produce.

  • Ehlers-Danlos Syndrome (EDS): A group of genetic disorders primarily affecting connective tissues, often due to defects in collagen synthesis or processing enzymes (e.g., hydroxylases).

    • Symptoms: Characterized by hyperflexible joints, stretchy skin, and fragile tissues. Individuals with EDS may exhibit extreme joint mobility and skin elasticity, sometimes exploited by contortionists or performers, but it is a medical condition.

Globular Proteins

• Function: Mostly serve as enzymes and other diverse cellular proteins.

• Structure Formation:

  • Primary Structure: The linear sequence of amino acids (N-terminal to C-terminal) dictates the final folded structure.

  • Folding: Driven by interactions between amino acids, often initiated at nucleation sites (regions with a high concentration of hydrophobic amino acids).

• Tertiary Structure (Three-Dimensional Shape): Composed of various secondary structures (alpha helices, beta sheets, turns) arranged into a compact, globular form.

• Stabilizing Interactions: The intricate 3D structure is stabilized by several types of interactions:

  • Non-covalent Interactions:

    1. Ionic Interactions (Salt Bridges): Electrostatic attractions between oppositely charged amino acid side chains.

    2. Hydrogen Bonds: Between polar side chains and backbone atoms.

    3. Hydrophilic Interactions: Interactions between polar residues and water or other polar molecules.

    4. Van der Waals Interactions: Weak, short-range attractive forces between all non-polar atoms.

  • Covalent Interactions:

    1. Disulfide Bonds (Sulfur-Sulfur Linkages): Covalent bonds formed between the sulfhydryl groups of two cysteine residues ($S-S$), often contributing to long-range stabilization.

• Domains and Function: Globular proteins often contain distinct domains (independently folding functional units).

  • Many globular proteins feature a substrate binding site (SBS), which is a specific region on the protein surface (often a cleft or pocket) where substrate molecules bind for enzymatic reactions or other cellular processes.