Tyrosine-type site-specific recombinases are ubiquitous in eubacteria,
prevalent in archaea and temperate phages and present in certain yeast
strains. They catalyze a variety of sequence-specific DNA rearrangements in
biological systems, including the integration and excision of phage genomes
into and out of their bacterial hosts, conjugative transposition, resolution
of catenated DNA circles, regulation of plasmid copy number, DNA excision to
control gene expression for nitrogen fixation in Anabaena and DNA inversions
controlling expression of cell surface proteins or DNA replication. Well
studied members of the family include the phage lambda integrase, responsible
for integration of the lambda phage genome, the phage P1 recombinase, involved
in cyclization of the P1 genome as well as resolution of genomic multimers,
the Escherichia coli XerC/XerD recombinases, responsible for resolution of
dimers of the bacterial chromosome, and the yeast Flp recombinase, responsible
for the control of plasmid copy number. Tyrosine recombinase family members
have the distinctive ability to carry out a complete site-specific
recombination reaction between two DNAs in the absence of high energy
cofactors. DNA cleavage and rejoining is accomplished in two steps. First, a
tyrosine hydroxyl attacks the scissile phosphate, nicking the DNA and forming
a 3' phosphotyrosine-linked DNA complex. This covalent protein-DNA
intermediate is resolved when the 5' terminal hydroxyl of the invading DNA
strand attacks the phosphotyrosine linkage and displaces the protein, forming
a holliday junction. The reaction is repeated for the other strand of each DNA
partner, generating the recombinant DNA duplexes. It is the transient covalent
linkage of protein and DNA that conserves the energy of the broken
phosphodiester bond, enabling a pair of reciprocal strand exchanges to proceed
[1,2,3,4,5].
The tyrosine recombinase catalytic domain spans ~180 amino acids and its
active site is composed of seven conserved residues: two arginine and
histidine residues, an aspartate or glutamate, a lysine and the essential
catalytic tyrosine residue. These residues play catalytic roles in several
enzymes. Specifically the Tyr and Lys serves as nucleophile and general acid
catalysts, respectively. The two Arg residues neutralize the negative charge
during the transition state and activate the scissile phosphate by the
catalytic tyrosine residue. Finally, the two His and the Glu/Asp residues
stabilize the transition state [2,6]. The core tyrosine recombinase catalytic
domain has a mixed α-β structure consisting of seven α helices and
seven β strands (see <PDB:<1AE9>). An α-helical bundle with an unusual
packing geometry is cradled by two antiparallel β hairpins [7]. The yeast
Flp tyrosine recombinase domain contains an additional C-terminal extension
not found in the core tyrosine recombinase domain of archaea, prokaryotes and
phages (see <PDB:1FLO>). This extension forms a β hairpin and three short
helices that pack onto the opposite face of the tyrosine recombinase core
domain from the DNA [8].
We developed two profiles for tyrosine recombinase domains. The first one
covers the entire core domain of prokaryotes, archaea and phages, whereas the
second covers the entire tyrosine recombinase domain of yeast, including its
C-terminal extension.
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