4 Three-Dimensional Structure of Proteins
functional protein
Native Environment
Ions, Cofactors, Chaperones, etc.
Pathway of protein folding. Normal folding occurs with the help of chaperones and other factors. Misfolding of
polypeptides can lead to targeting to inappropriate cellular locations, or to degradation as a part of the quality control
process, or to aggregation. The aggregated product is often resistant to proteolysis and forms aggregates, such as
amyloid plaques.
associated with a functional protein. The process of direct-
ing and targeting the folding of intermediate polypeptides
to the fully folded structures is aided, in some instances,
by proteins known as
molecular chaperones
(also called
(Figure 4-13).
Chaperones bind reversibly to unfolded polypeptide
segments and prevent their misfolding and premature ag-
gregation. This process involves energy expenditure pro-
vided by the hydrolysis of ATP. A major class of chaper-
ones is
heat-shock proteins
(hsp), which are synthesized
in both prokaryotic and eukaryotic cells in response to heat
shock or other stresses (e.g., free-radical exposure). There
are many classes of heat-shock chaperones (HSP-60, HSP-
70, and HSP-90) that are present in various organelles
of the cell. HSP-70 chaperones contain two domains: an
ATPase domain and a peptide binding domain. They sta-
bilize nascent polypeptides and also are able to reconform
denatured forms of polypeptides. The HSP-70 family of
chaperones shows a high degree of sequence homology
among various species (e.g.,
E. coli
and human HSP-70
proteins show 50% sequence homology).
Another chaperone,
is a 90 kDa Ca2+-binding
protein and is an integral membrane phosphoprotein of ER.
Calnexin monitors the export of newly synthesized glyco-
proteins by complexing with misfolded glycoproteins that
have undergone glycosylation (Chapter 16). If a protein
cannot be folded into its proper conformation, chaperones
assist in destruction. The process of folding is also facil-
itated by the ionic environment, cofactors, and enzymes.
For example, folding is affected by protein disulfide iso-
merase, which catalyzes the formation of correct disulfide
linkages, and by peptidyl prolyl isomerases, which cat-
alyze the cis-trans isomerization of specific amino acid-
proline peptide bonds.
Several disorders of protein folding are known that have
the characteristic pathological hallmark of protein aggre-
gation and deposits in and around the cells. The protein
deposits are called amyloid and the disease is known as
Protein folding diseases, also known as con-
formational diseases, have many different etiologies, such
as changes in the primary structure of proteins, defects in
chaperones, and the inappropriate presence or influence
of other proteins. A list of protein folding disorders is
given in Table 4-1; some are discussed below and others
in subsequent chapters. A common though not invariable
aspect of conformational protein diseases is that the aggre-
gation of polypeptides is made up of
is primarily due to a transition from a-helical structure
to ^-structure. Another feature is that the aggregates are
resistant to normal proteolysis.
A dementia syndrome characterized by an insidious
progressive decline in memory, cognition, behavioral
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