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Amyloidin and protein native state structures

Posted by pbio on 07 May 2009 at 22:12 GMT

Author: Antonio Trovato
Institution: Physics Department 'G. Galilei', Padova University and INFN, Padova, Italy
Additional Authors: Jayanth R. Banavar, Trinh X. Hoang, Amos Maritan, Flavio Seno
Submitted Date: December 06, 2005
Published Date: December 27, 2005
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

J.R. Banavar, T.X. Hoang, A. Maritan, F. Seno and A. Trovato.

Fowler et al. (1) have recently demonstrated that native amyloid or
amyloidin is a key protein structural motif employed by living
organisms and they suggest that the usage of amyloid in biology may be
as common as other canonical protein folds. This finding is in perfect
accord with a recent theoretical prediction (2) derived from a unified
framework (2-5) for understanding protein folding, amyloid formation,
and protein interactions.

The unified framework builds on the identification of a novel phase of
matter used by nature to house both the native state folds as well as
the amyloidin structure. This unusual phase occurs in a simple
physical system of a flexible tube (2-5), subject to attractive
self-interactions promoting compaction and to amino acid aspecific
geometrical constraints arising from hydrogen bonds, and allows one to
understand the stunning common characteristics of proteins: symmetry
and geometry determine the limited menu of folded conformations that a
protein can choose from for its native state structure; these
structures are in a marginally compact phase in the vicinity of a
phase transition and are therefore eminently suited for biological
function; these pre-determined folds are the molecular target for the
powerful forces of evolution; proteins are well-designed sequences of
amino acids which fit well into one of these predetermined folds; and
the amyloidin structure is a natural consequence of the unified
framework (see e.g. Fig.10 of ref. (2)). It is especially pleasing
that Fowler et al. (1) have now shown that nature has used the
amyloidin structure positively.

The native states of globular proteins are housed in modular
structures commonly built of helices and sheets, which are repetitive
motifs for which hydrogen bonds provide the scaffolding (6,7). Steric
effects also encourage the polypeptide chain to adopt either the
helical or the extended conformation (8). The tube picture provides a
link between the unrelated mechanisms of hydrogen bonds and sterics,
both of which conspire to promote secondary motifs.

In a recent paper, Fandrich and Dobson (9) stated that ``amyloid
formation and protein folding represent two fundamentally different
ways of organizing polypeptides into ordered conformations. Protein
folding depends critically on the presence of distinctive side chain
sequences and produces a unique globular fold. By contrast,
. . . amyloid formation arises primarily from main chain interactions
that are, in some environments, overruled by specific side chain
contacts. Our results are in complete accord with the suggestion
that amyloid structures arise from the generic properties of the
proteins with the details of the amino acid side chains playing a
secondary role. However, our work suggests that instead of an
``inverse side chain effect in amyloid structure formation
there is a unifying theme in the behavior of proteins. Just as the
class of cross-linked amyloidin structures is determined from
geometrical considerations, the menu of protein native state folds
also results from the common attributes of globular proteins and acts
as a fixed backdrop for the evolution of sequences and

(1) Fowler DM, et al. (2006) PLOS Biology 4, 1.
(2) Banavar JR, et al. (2004), Phys. Rev. E70, 041905.
(3) Maritan A, Micheletti C, Trovato A, and Banavar JR, (2000) Nature 406, 287.
(4) Banavar JR and Maritan A, (2003) Rev. Mod. Phys. 75, 23.
(5) Hoang TX, et al. (2004), P. Natl. Acad. Sci. USA 101, 7960.
(6) Pauling L, Corey RB, and Branson HR (1951) P. Natl. Acad. Sci. USA 37, 205.
(7) Pauling L and Corey RB, (1951) P. Natl. Acad. Sci. USA 37, 729.
(8) Ramachandran GN and Sasisekharan V, (1968) Adv. Protein Chem. 23, 283.
(9) Fandrich M and Dobson CM, (2002) EMBO 21, 5682.

No competing interests declared.