This preview shows pages 1–2. Sign up to view the full content.
This preview has intentionally blurred sections. Sign up to view the full version.View Full Document
Unformatted text preview: The FASEB Journal • Review Molecular and cellular aspects of protein misfolding and disease Eszter Herczenik* and Martijn F. B. G. Gebbink* ,†,1 *Laboratory of Thrombosis and Haemostasis, Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, The Netherlands; and † Crossbeta Biosciences BV, Utrecht, The Netherlands ABSTRACT Proteins are essential elements for life. They are building blocks of all organisms and the operators of cellular functions. Humans produce a repertoire of at least 30,000 different proteins, each with a different role. Each protein has its own unique sequence and shape (native conformation) to fulfill its specific function. The appearance of incorrectly shaped (misfolded) proteins occurs on exposure to environmental changes. Protein misfolding and the subsequent aggregation is associated with various, of- ten highly debilitating, diseases for which no sufficient cure is available yet. In the first part of this review we summarize the structural composition of proteins and the current knowledge of underlying forces that lead proteins to lose their native structure. In the second and third parts we describe the molecular and cellular mechanisms that are associated with protein misfolding in disease. Finally, in the last part we portray recent efforts to develop treatments for protein misfolding diseases.—Herczenik, E., and Gebbink, M. F. B. G. Molecular and cellular aspects of protein misfolding and disease. FASEB J. 22, 2115–2133 (2008) Key Words: protein structure z aggregation z amyloid z Alzhei- mer’s disease z atherosclerosis z therapy THE APPEARANCE OF PROTEINS The structure of proteins Proteins are molecules composed of an amino acid chain, in which each amino acid is connected to the next one by a peptide bond. Proteins are very diverse and vary in size from small peptides to large multimers. The common element of proteins is the peptide back- bone formed by peptide bonds that link the amino acids. The variation among peptides is related to the sequence of the amino acids and their side groups. There are 20 different amino acids, and they have either acidic, basic, neutral, or hydrophobic side chains. The order of the amino acids determines the primary structure of the protein by creating a unique polypeptide chain, which is relatively flexible ( Fig. 1 ). Polypeptides can fold into three secondary elements: the a-helix and the b-sheet, which determine the three- dimensional structure of the protein, and the random coil, which has less ordered interchain amino acid side chain interactions, leaving free rotation around each bond. The tertiary structure refers to the distribution of the a-helices and b-sheets and random coils in the protein, wherein these elements are folded into a compact conformation stabilized by hydrogen bonds or ionic interactions. The term quaternary structure is used for the description of multimeric proteins, in which the different polypeptide chains are connected.different polypeptide chains are connected....
View Full Document