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

PROTEIN FUNCTION
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We can gain some idea of the complexity of intracellular protein networks
from a particularly well-studied example described in Chapter 16: the many dozens
of proteins that interact with the actin cytoskeleton to control actin filament
behavior (see Panel 16–3, p. 905).
The extent of such protein–protein interactions can also be estimated more
generally. An enormous amount of valuable information is now freely available in
protein databases on the Internet: tens of thousands of three-dimensional protein
structures plus tens of millions of protein sequences derived from the nucleotide
sequences of genes. Scientists have been developing new methods for mining
this great resource to increase our understanding of cells. In particular, computer-based
bioinformatics tools are being combined with robotics and other technologies
to allow thousands of proteins to be investigated in a single set of experiments.
Proteomics is a term that is often used to describe such research focused
on the analysis of large sets of proteins, analogous to the term genomics describing
the large-scale analysis of DNA sequences and genes.
A biochemical method based on affinity tagging and mass spectroscopy
has proven especially powerful for determining the direct binding interactions
between the many different proteins in a cell (discussed in Chapter 8). The results
are being tabulated and organized in Internet databases. This allows a cell biologist
studying a small set of proteins to readily discover which other proteins in the
same cell are likely to bind to, and thus interact with, that set of proteins. When
displayed graphically as a protein interaction map, each protein is represented by
a box or dot in a two-dimensional network, with a straight line connecting those
proteins that have been found to bind to each other.
When hundreds or thousands of proteins are displayed on the same map, the
network diagram becomes bewilderingly complicated, serving to illustrate the
enormous challenges that face scientists attempting to understand the cell (Figure
3–80). Much more useful are small subsections of these maps, centered on a
few proteins of interest.
We have previously described the structure and mode of action of the SCF
ubiquitin ligase, using it to illustrate how protein complexes are constructed from
interchangeable parts (see Figure 3–71). Figure 3–81 shows a network of protein–
protein interactions for the five proteins that form this protein complex in a yeast
cell. Four of the subunits of this ligase are located at the bottom right of this figure.
The remaining subunit, the F-box protein that serves as its substrate-binding arm,
appears as a set of 15 different gene products that bind to adaptor protein 2 (the
Skp1 protein). Along the top and left of the figure are sets of additional protein
interactions marked with yellow and green shading: as indicated, these protein
sets function at the origin of DNA replication, in cell cycle regulation, in methionine
synthesis, in the kinetochore, and in vacuolar H + -ATPase assembly. We
shall use this figure to explain how such protein interaction maps are used, and
what they do and do not mean.
1. Protein interaction maps are useful for identifying the likely function of
previously uncharacterized proteins. Examples are the products of the
genes that have thus far only been inferred to exist from the yeast genome
sequence, which are the three proteins in the figure that lack a simple
three-letter abbreviation (white letters beginning with Y). The three in this
diagram are F-box proteins that bind to Skp1; these are therefore likely to
function as part of the ubiquitin ligase, serving as substrate-binding arms
that recognize different target proteins. However, as we discuss next, neither
assignment can be considered certain without additional data.
2. Protein interaction networks need to be interpreted with caution because,
as a result of evolution making efficient use of each organism’s genetic
information, the same protein can be used as part of different protein
complexes that have different types of functions. Thus, although protein A
binds to protein B and protein B binds to protein C, proteins A and C need
not function in the same process. For example, we know from detailed
biochemical studies that the functions of Skp1 in the kinetochore and in
Figure 3–80 A network of proteinbinding
interactions in a yeast cell.
Each line connecting a pair of dots
(proteins) indicates a protein–protein
interaction. (From A. Guimerá and
M. Sales–Pardo, Mol. Syst. Biol. 2:42,
2006. With permission from Macmillan
Publishers Ltd.)
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