Structure, function and evolution of multidomain proteins
Christine Vogel, Matthew Bashton, Nicola D Kerrison, Cyrus
Chothia and Sarah A Teichmann
Current Opinion in Structural Biology 2004, 14:208-216
Proteins are composed of evolutionary units called domains;
the majority of proteins consist of at least two domains.
These domains and nature of their interactions determine the
function of the protein. The roles that combinations of
domains play in the formation of the protein repertoire have
been found by analysis of domain assignments to genome
sequences. Additional findings on the geometry of domains
have been gained from examination of three-dimensional
protein structures. Future work will require a domain-
centric functional classification scheme and efforts to
determine structures of domain combinations.
Introduction
There are various uses of the word domain with respect to
proteins. Here, we define a protein domain as an
independent, evolutionary unit that can form a single-domain
protein or be part of one or more different multidomain
proteins. The domain can either have an independent function
or contribute to the function of a multidomain protein in
cooperation with other domains. The definition of a domain
as an evolutionary unit is used in the Structural
Classification of Proteins (SCOP) database [1].
In SCOP, domains that have a common ancestor based on
sequence, structural and functional evidence are grouped
into superfamilies. There are more than 1200 domain
superfamilies in the current version of the database [2],
though estimates of the total number of superfamilies vary
from a few to several thousand [3-5] . Domains from the
superfamilies in SCOP can be assigned to 40-60% of the
residues in the proteins of completely sequenced genomes
using homology-based methods. These include the profile
hidden Markov models in the SUPERFAMILY database [6,7.] ,
the structural profiles of the PSSM server
[8], the PSI-BLAST profiles in the Gene3D database [9] or
combined approaches [10.]. From the assignment of
structural domains to genome sequences, it is clear that
some two-thirds of proteins consist of two or more
domains in prokaryotes [11] and an even larger fraction
in eukaryotes
[9].
As most proteins consist of multiple domains, and domains
determine the function and evolutionary relationships of
proteins, it is important to understand the principles of
domain combinations and interactions. In this review, we
discuss how domain superfamilies form the repertoire of
multidomain proteins via duplication and recombination (
Figure 1). We then describe the principles and extent of
conservation of the N- to C-terminal order of domains, their
three-dimensional geometry and their functional
relationships. This will illustrate the importance of domain
combinations to an understanding of protein evolution,
structure and function, and to target selection in
structural genomics.
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