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

160 Chapter 3: Proteins
adaptor
protein 2
F-box protein
(substrate-binding arm)
E2 ubiquitinconjugating
enzyme
target protein
ubiquitin
APC/C
adaptor
protein 1
TARGET PROTEIN
BINDS
(A)
scaffold protein
(cullin)
substrate-binding
two of many
possible
substrate-binding
arms
polyubiquitylated
protein targeted
for destruction
SCF
E2-binding
(B) (C) ubiquitin ligase
(D)
10 nm
In this manner, specific proteins are targeted for rapid destruction in response
to specific signals, thereby helping to drive the cell cycle (discussed in Chapter 17).
The timing of the destruction often involves creating a specific pattern of phosphorylation
on the target protein that is required for its recognition by the F-box
MBoC6 m3.79/3.66
subunit. It also requires the activation of an SCF ubiquitin ligase that carries the
appropriate substrate-binding arm. Many of these arms (the F-box subunits) are
interchangeable in the protein complex (see Figure 3–71B), and there are more
than 70 human genes that encode them.
As emphasized previously, once a successful protein has evolved, its genetic
information tends to be duplicated to produce a family of related proteins. Thus,
for example, not only are there many F-box proteins—making possible the recognition
of different sets of target proteins—but there is also a family of scaffolds
(known as cullins) that give rise to a family of SCF-like ubiquitin ligases.
A protein machine like the SCF ubiquitin ligase, with its interchangeable parts,
makes economical use of the genetic information in cells. It also creates opportunities
for “rapid” evolution, inasmuch as new functions can evolve for the entire
complex simply by producing an alternative version of one of its subunits.
Ubiquitin ligases form a diverse family of protein complexes. Some of these
complexes are far larger and more complicated than SCF, but their underlying
enzymatic function remains the same (Figure 3–71D).
A GTP-Binding Protein Shows How Large Protein Movements
Can Be Generated
Detailed structures obtained for one of the GTP-binding protein family members,
the EF-Tu protein, provide a good example of how allosteric changes in protein
conformations can produce large movements by amplifying a small, local conformational
change. As will be discussed in Chapter 6, EF-Tu is an abundant molecule
that serves as an elongation factor (hence the EF) in protein synthesis, loading
each aminoacyl-tRNA molecule onto the ribosome. EF-Tu contains a Ras-like
domain (see Figure 3–67), and the tRNA molecule forms a tight complex with its
GTP-bound form. This tRNA molecule can transfer its amino acid to the growing
Figure 3–71 The structure and mode of
action of an SCF ubiquitin ligase. (A) The
structure of the five-protein ubiquitin ligase
complex that includes an E2 ubiquitinconjugating
enzyme. Four proteins form the
E3 portion. The protein denoted here as
adaptor protein 1 is the Rbx1/Hrt1 protein,
adaptor protein 2 is the Skp1 protein, and
the cullin is the Cul1 protein. One of the
many different F-box proteins completes
the complex. (B) Comparison of the same
complex with two different substrate-binding
arms, the F-box proteins Skp2 (top) and
β-trCP1 (bottom), respectively. (C) The
binding and ubiquitylation of a target protein
by the SCF ubiquitin ligase. If, as indicated,
a chain of ubiquitin molecules is added to
the same lysine of the target protein, that
protein is marked for rapid destruction by the
proteasome. (D) Comparison of SCF (bottom)
with a low-resolution electron microscopy
structure of a ubiquitin ligase called the
anaphase-promoting complex (APC/C; top)
at the same scale. The APC/C is a large,
15-protein complex. As discussed in Chapter
17, its ubiquitylations control the late stages
of mitosis. It is distantly related to SCF and
contains a cullin subunit (green) that lies along
the side of the complex at right, only partly
visible in this view. E2 proteins are not shown
here, but their binding sites are indicated in
orange, along with substrate-binding sites
in purple. (A and B, adapted from G. Wu
et al., Mol. Cell 11:1445–1456, 2003. With
permission from Elsevier; D, adapted from
P. da Fonseca et al., Nature 470:274–278,
2011. With permission from Macmillan
Publishers Ltd.)