Biology Reference
In-Depth Information
of conformation. Seen from this perspective, it is not the pre-exist-
ing structure of the protein which determines its future interactions
but the ligand, which stabilises one of these conformations and
alters the equilibrium of the population (Ma
et al.,
2002).
4.2.3
Molecular disorder
There is an even more radical cause of molecular non-specificity. We
have already emphasised the fact that molecular biology is based on
the idea that proteins have a well-defined three-dimensional struc-
ture, and that macroscopic biological organisation arises from this
microscopic order. This dogma has now been demolished. It has
been shown that a large fraction of proteomes correspond to pro-
teins which contain intrinsically disordered regions, incapable of
generating secondary and therefore stable, three-dimensional struc-
tures by themselves. The disordered regions comprise in general
more than half of each of these proteins and often their entirety.
They are not of secondary importance. On the contrary, proteins
only acquire a functional structure when the disordered regions are
stabilized by interaction with another molecule. Owing to their
great plasticity, they can interact with a large number of partners
adopting a different configuration and function in each case (Wright
and Dyson, 1999; Dunker and Obradovic, 2001; Dyson and Wright,
2005; Dunker
et al
., 2005). For example, HMGA is a nuclear pro-
tein which is intrinsically totally disordered. It has an important
role in structuring chromosomes and chromatin, and in the tran-
scription of at least 45 genes. To perform this role it interacts with
the chromosomal structures, the nucleosomes, and with at least 18
different transcription factors. In each case interaction with a
different partner confers on it a particular functional structure.
Another well-known example involving a fundamental biological
function is protein p21 which is known for its essential role in the
cell cycle. It inhibits a variety of molecular (cyclin-Cdk) complexes
thanks to variable conformations stabilised by the interactions. These
are not isolated cases. Today, we know of hundreds of proteins
