Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

354 Chapter 6: How Cells Read the Genome: From DNA to Protein
Figure 6–77 Steps in the creation of a functional protein. As indicated,
translation of an mRNA sequence into an amino acid sequence on the
ribosome is not the end of the process of forming a protein. To function, the
completed polypeptide chain must fold correctly into its three-dimensional
conformation, bind any cofactors required, and assemble with its partner
protein chains, if any. Noncovalent bond formation drives these changes.
As indicated, many proteins also require covalent modifications of selected
amino acids. Although the most frequent modifications are protein
glycosylation and protein phosphorylation, over 200 different types of
covalent modifications are known (see pp. 165–166).
nascent polypeptide chain
folding and
cofactor binding
(noncovalent
interactions)
protein folds into a compact structure, it buries most of its hydrophobic residues
in an interior core. In addition, large numbers of noncovalent interactions form
between various parts of the molecule. It is the sum of all of these energetically
favorable arrangements that determines the final folding pattern of the polypeptide
chain—as the conformation of lowest free energy (see pp. 114–115).
Through many millions of years of evolution, the amino acid sequence of each
protein has been selected not only for the conformation that it adopts but also
for an ability to fold rapidly. For some proteins, this folding begins immediately,
as the protein chain emerges from the ribosome, starting from the N-terminal
end. In these cases, as each protein domain emerges from the ribosome, within
a few seconds it forms a compact structure that contains most of the final secondary
features (α helices and β sheets) aligned in roughly the right conformation
(Figure 6–78). For some protein domains, this unusually dynamic and flexible
state, called a molten globule, is the starting point for a relatively slow process in
which many side-chain adjustments occur that eventually form the correct tertiary
structure. It takes several minutes to synthesize a protein of average size, and
for some proteins much of the folding process is complete by the time the ribosome
releases the C-terminal end of a protein (Figure 6–79).
covalent modification
by glycosylation,
phosphorylation,
acetylation etc.
binding to other
protein subunits
mature functional protein
P
P
Molecular Chaperones Help Guide the Folding of Most Proteins
Most proteins probably do not fold correctly during their synthesis and require a
special class of proteins called molecular chaperones to do so. Molecular chaperones
are useful for cells because there are many different folding paths available
to an unfolded or partially folded protein. Without chaperones, some of these
pathways would not lead to the correctly folded (and most stable) form because
the protein would become “kinetically trapped” in structures that are off-pathway.
Some of these off-pathway configurations would aggregate and be left as irreversible
dead ends of nonfunctional (and potentially dangerous) structures.
MBoC6 m6.82/6.77
(A)
(B)
Figure 6–78 The structure of a molten
globule. (A) A molten globule form of
cytochrome b 562 is more open and less
highly ordered than the final folded form
of the protein, shown in (B). Note that
the molten globule contains most of the
secondary structure of the final form,
although the ends of the α helices are
unraveled and one of the helices is only
partly formed. (Courtesy of Joshua Wand,
from Y. Feng et al., Nat. Struct. Biol. 1:30–
35, 1994. With permission from Macmillan
Publishers Ltd.)