The World of Functional Amyloid - The Functional Fold: Amyloid Structures in Nature - page 2

1.1 Protein Misfolding and Aggregation

Proteins are linear biopolymers composed of amino acid monomers
that carry out a wide range of functions. Proteins generally adopt
well-defined, three-dimensional structures as a consequence of
their sequence and their environment.

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While numerous natively
unfolded examples exist, proper protein function typically depends
on forming the correct three-dimensional structure. This process is
known as protein folding.
Protein folding is a highly complex conformational transforma-
tion that converts an ensemble of largely orderless protein structures
(random coil) into an ensemble of compact, well-defined structures
(globular fold). Protein structure is dictated by the specific amino
acid sequence of a given polypeptide, the general features of the
polypeptide backbone and the environment in which it folds
including the aqueous solvent and the presence of chaperones,
folding enzymes, and the like. Backbone conformational and
hydrogen bonding preferences favour the formation of three types
of generalized conformation-reverse turns,

α β

-sheets.
Thus, protein folding is a spontaneous, intramolecular process
typically occurring on a short timescale that yields functional protein
molecules.

-helices, and

Despite eons of evolutionary fine-tuning, the protein folding
process is always in competition with misfolding and aggregation.
Like intramolecular protein folding, intermolecular aggregation
is influenced by the conformational requirements of the amide
backbone as well as the amino acid composition, the environment
and the polypeptide conformation. Thus, aggregates with specific
quaternary structures (

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α β

-helical or -sheet) can be formed. Amyloid

is a compact, fibrous, and -sheet-rich protein quaternary structure

that, until recently, was solely linked to a variety of degenerative
diseases.

β

1. Structural Properties of Amyloid

Amyloid fibres are formed by the self-assembly of protein or
peptide monomers into intermolecularly hydrogen bonded

β

-sheets

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(Fig. 1.1a,c). The amyloid fold is sometimes called a cross-

β

-sheet

β

quaternary structure because -strands are oriented perpendicular