60

chapter

4 Three-Dimensional Structure of Proteins

Protein

synthesis

Folded,

functional protein

N

N

Native Environment

Ions, Cofactors, Chaperones, etc.

FIGURE 4-13

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

chaperonins)

(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,

calnexin,

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

amyloidosis.

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

(3-structures.

This

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