Proteins and Protein Structure

Protein Structure

• Proteins have a linear sequence of linked amino acids, which contains the information necessary to generate a protein molecule with a unique three-dimensional shape.
• The complexity of protein structure is best analyzed by considering the molecule in terms of four organizational levels: primary, secondary, tertiary, and quaternary.

Primary Structure

• The primary structure of a protein is the sequence of amino acids in a protein.
• It is required for understanding a protein's structure, its mechanism of action at a molecular level, and its relationship to other proteins with similar physiological roles.
• Many genetic diseases result in proteins with abnormal amino acid sequences, which cause improper folding and loss or impairment of normal function.

Secondary Structure

• The secondary structure of a protein is the regular arrangement of amino acids that are located near to each other in the linear sequence.
• Examples of secondary structures frequently encountered in proteins include:
  • α-helix (a spiral structure, tightly packed, coiled polypeptide backbone core, and side chains extending outward from the central axis)
  • β-sheet (a zigzag structure, hydrogen bonds formed between adjacent segments of polypeptide chain)
  • β-bend (a connecting element that links successive runs of α-helix or β-conformation)

Tertiary Structure

• The tertiary structure of a protein is the overall 3D shape of the protein molecule.
• It is determined by the primary structure of a polypeptide chain.
• Globular proteins have a compact, high-density core with hydrophobic side chains buried in the interior and hydrophilic groups on the surface.

Protein Folding

• Protein folding occurs within the cell in seconds to minutes and employs a shortcut through the maze of all folding possibilities.
• Interactions between the side chains of amino acids determine how a long polypeptide chain folds into the intricate three-dimensional shape of the functional protein.
• Cells contain enzymes that facilitate the folding process, including cis-trans prolyl isomerases, protein disulfide isomerases, and chaperone proteins.

Protein Misfolding

• Deposits of misfolded proteins are associated with a number of diseases, including amyloidoses.
• Examples of protein misfolding diseases include:
  • Alzheimer disease
  • Transthyretin amyloidosis cardiomyopathy (ATTR)
  • Transmissible spongiform encephalopathies (TSEs), including Creutzfeldt-Jakob disease, scrapie, and bovine spongiform encephalopathy (mad cow disease)

Transthyretin Amyloidosis (ATTR)

• ATTR occurs as a result of misfolding of transthyretin protein produced by the liver.
• It produces amyloid fibrils that can deposit in various tissues, causing irreversible damage.
• Mutation in the gene coding for TTR can cause structural changes leading to misfolding (hATTR).
• The wild-type ATTR is common in 25% of patients over 80 years.
• Transthyretin Amyloidosis cardiomyopathy (ATTR-CM) is a systemic amyloidosis caused by accumulation of tranthyretin fibril in the myocardium.