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Tertiary Structure
The tertiary structure refers to the overall three-dimensional conformation of a single polypeptide chain, arising from the folding and spatial arrangement of its secondary structural elements (α-helices, β-sheets, turns, and loops) into a compact, functionally active form. Unlike the repetitive patterns of secondary structure, tertiary structure is unique to each protein and directly determines its biological function.
Forces Driving Tertiary Structure
Hydrophobic Interactions
Nonpolar side chains (e.g., leucine, isoleucine, valine, phenylalanine) cluster in the protein interior to avoid contact with water.
Major driving force in protein folding.
Hydrogen Bonds
Occur between polar side chains and/or backbone atoms.
Stabilize both internal arrangements and interactions with solvent molecules.
Ionic Interactions (Salt Bridges)
Form between oppositely charged residues (e.g., lysine–glutamate).
Often stabilize surface regions of proteins.
Van der Waals Forces
Weak, nonspecific interactions between closely packed atoms.
Contribute significantly due to the dense packing of protein interiors.
Disulfide Bonds
Covalent bonds between cysteine residues (–SH → –S–S–).
Provide stability against denaturation, common in extracellular proteins (e.g., insulin).
Structural Motifs (Supersecondary Structures)
Tertiary structures often contain recurrent folding patterns called motifs, which are combinations of secondary structures with specific topologies and functions:
Helix-turn-helix: common in DNA-binding proteins.
Leucine zipper: dimerization motif in transcription factors.
β-barrel: cylindrical structure in membrane proteins and transporters.
Rossmann fold: nucleotide-binding motif in enzymes.
Protein Domains
Definition: Independently folded, stable units within a single polypeptide.
Characteristics:
Typically 50–250 amino acids long.
Can function independently or cooperate with other domains.
Examples:
SH2 and SH3 domains in signaling proteins.
Immunoglobulin domains in antibodies.
Domains are evolutionary building blocks that enable modularity and functional diversity.
Folding Pathways
Protein folding is co-translational, beginning as the nascent chain emerges from the ribosome.
Small peptides may fold spontaneously, but larger proteins require molecular chaperones (e.g., Hsp70, chaperonins).
Folding follows a pathway from unfolded → molten globule → native state, minimizing free energy.
Misfolding can result in aggregation and diseases such as Alzheimer’s (Aβ plaques), Parkinson’s (α-synuclein), and prion diseases.
Experimental Determination of Tertiary Structure
X-ray crystallography: high-resolution structural determination; requires crystallization.
NMR spectroscopy: used for smaller proteins (<30 kDa) in solution.
Cryo-electron microscopy (cryo-EM): increasingly important for large complexes.
Computational modeling: advances like AlphaFold predict tertiary structures with remarkable accuracy.
Biological Relevance
The tertiary structure defines the active site geometry of enzymes.
Determines binding specificity for ligands, substrates, and regulatory molecules.
Facilitates protein-protein interactions in cellular pathways.
Structural flexibility enables allosteric regulation, where binding at one site modulates function at another.
The tertiary structure refers to the overall three-dimensional conformation of a single polypeptide chain, arising from the folding and spatial arrangement of its secondary structural elements (α-helices, β-sheets, turns, and loops) into a compact, functionally active form. Unlike the repetitive patterns of secondary structure, tertiary structure is unique to each protein and directly determines its biological function.
Forces Driving Tertiary Structure
Hydrophobic Interactions
Nonpolar side chains (e.g., leucine, isoleucine, valine, phenylalanine) cluster in the protein interior to avoid contact with water.
Major driving force in protein folding.
Hydrogen Bonds
Occur between polar side chains and/or backbone atoms.
Stabilize both internal arrangements and interactions with solvent molecules.
Ionic Interactions (Salt Bridges)
Form between oppositely charged residues (e.g., lysine–glutamate).
Often stabilize surface regions of proteins.
Van der Waals Forces
Weak, nonspecific interactions between closely packed atoms.
Contribute significantly due to the dense packing of protein interiors.
Disulfide Bonds
Covalent bonds between cysteine residues (–SH → –S–S–).
Provide stability against denaturation, common in extracellular proteins (e.g., insulin).
Structural Motifs (Supersecondary Structures)
Tertiary structures often contain recurrent folding patterns called motifs, which are combinations of secondary structures with specific topologies and functions:
Helix-turn-helix: common in DNA-binding proteins.
Leucine zipper: dimerization motif in transcription factors.
β-barrel: cylindrical structure in membrane proteins and transporters.
Rossmann fold: nucleotide-binding motif in enzymes.
Protein Domains
Definition: Independently folded, stable units within a single polypeptide.
Characteristics:
Typically 50–250 amino acids long.
Can function independently or cooperate with other domains.
Examples:
SH2 and SH3 domains in signaling proteins.
Immunoglobulin domains in antibodies.
Domains are evolutionary building blocks that enable modularity and functional diversity.
Folding Pathways
Protein folding is co-translational, beginning as the nascent chain emerges from the ribosome.
Small peptides may fold spontaneously, but larger proteins require molecular chaperones (e.g., Hsp70, chaperonins).
Folding follows a pathway from unfolded → molten globule → native state, minimizing free energy.
Misfolding can result in aggregation and diseases such as Alzheimer’s (Aβ plaques), Parkinson’s (α-synuclein), and prion diseases.
Experimental Determination of Tertiary Structure
X-ray crystallography: high-resolution structural determination; requires crystallization.
NMR spectroscopy: used for smaller proteins (<30 kDa) in solution.
Cryo-electron microscopy (cryo-EM): increasingly important for large complexes.
Computational modeling: advances like AlphaFold predict tertiary structures with remarkable accuracy.
Biological Relevance
The tertiary structure defines the active site geometry of enzymes.
Determines binding specificity for ligands, substrates, and regulatory molecules.
Facilitates protein-protein interactions in cellular pathways.
Structural flexibility enables allosteric regulation, where binding at one site modulates function at another.