PROSITE documentation PDOC00333
View entry in NiceDoc formatView entry in raw text format (no links)
{PDOC00333}
{PS00396; TOPO_IA_1}
{PS52039; TOPO_IA_2}
{BEGIN}
***********************************************************************************
* Topoisomerase (Topo) IA-type active site signature and catalytic domain profile *
***********************************************************************************
DNA topoisomerases (Topos) are enzymes that solve topological problems
associated with important processes such as DNA replication, transcription,
recombination and chromatin remodeling by introducing transient single or
double stranded breaks in the DNA and releasing accumulated strain. They may
have appeared early during the formation of the modern DNA world. Several
families and subfamilies of the two types of DNA topoisomerases (I and II)
have been described in the three cellular domains of life (Archaea, Bacteria
and Eukarya), as well as in viruses infecting eukaryotes or bacteria. The main
families of DNA topoisomerases, Topo IA, Topo IB, Topo IC (Topo V), Topo IIA
and Topo IIB (Topo VI) are not homologous, indicating that they originated
independently. However, some of them share homologous modules or subunits that
were probably recruited independently to produce different topoisomerase
activities [1,2,3,4,5,6].
Type I topoisomerases are enzymes that effect topological changes on DNA by
transiently cleaving one DNA strand at a time. All Topo I use the same general
chemistry to break the phosphodiester bond. A tyrosyl group of the enzyme
attacks a phosphodiester bond on DNA and remains covalently attached to one
side of the break while releasing a free hydroxylated strand. The attack of
the phosphotyrosine bond by the hydroxyl end of the free strand restores a
phosphodiester bond and releases the enzyme for the next catalytic cycle. As
the energy of the phosphodiester bond is conserved in the protein-DNA covalent
intermediate, the cleavage-religation step does not require ATP hydrolysis.
Type I topoisomerases were further divided into two families, IA and IB (see
<PDOC00159>), on the basis of the polarity of strand cleavage. Topo IA form a
transient 5'-phospho-tyrosine covalent intermediate and release a free 3'-OH
strand whereas Topo IB form a 3'-phospho-tyrosine covalent intermediate and
release a free 5'-OH strand. The division between Topo IA and Topo IB is
supported by the absence of sequence or structural similarity between these
two enzyme families, thus indicating independent origin [1,2,3,4,5,6].
Topo IA are widespread in all domains of life, from bacteria to archaea and
higher eukaryotes. They share a common mechanism known as "enzyme-bridged
strand passage". Topo IA catalyse the cleavage of a single-strand DNA, forming
a transient 5'-phosphotyrosine covalent complex. The other DNA end is not free
to rotate but rather bound to the enzyme, thus allowing the passage of another
DNA strand through the break prior to rejoining of the DNA ends. The overall
reaction cycle is Mg(2+) dependent and results in the modification of DNA
topology strictly by steps of one. All Topo IA promote a partial relaxation of
negatively, but not positively supercoiled DNA, most likely because these
enzymes require an exposed single-strand region within the substrate DNA. In
addition to DNA relaxation, Topo IA can catalyse the knotting, unknotting and
interlinking of single-strand DNA circles as well as the knotting, unknotting
and catenation/decatenation of nicked double-strand DNAs. The Topo IA family
is divided into five subfamilies corresponding to (i) bacterial topoisomerase
I (Topo I), (ii) bacterial Topo III, (iii) eukaryal Topo III, (iv) archaeal
Type I DNA topoisomerases (annotated either as Topo I or Topo III), and (v)
reverse gyrase present in hyperthermophilic archaea and bacteria
[1,2,3,4,5,6].
The type IA topoisomerase core region is divided into four subdomains (I or
TOPRIM (see <PDOC50880>), II, III and IV), where subdomains II and IV result
from two separated regions in the protein primary sequence, which come
together in the three-dimensional structure. The Topo IA-type catalytic domain
consisting of subdomains III, II and IV exhibits a typical toroidal shape with
a central hole able to accommodate single-strand or double-strand DNA.
Subomain II forms over half of the torus and achieves its curvature through
several beta strands. Subdomain III is mainly helical and the last subdomain,
IV, forms part of the main body (see <PDB:1D6M>). There are two potential
flexible regions making the toroidal structure free to open: the first between
subdomains II and IV, the second between subdomains II and III. The active
site is at the interface between domain I (TOPRIM domain, see <PDOC50880>) and
domain III, while the single-stranded DNA to be cleaved is accommodated in the
groove at the interface of the TOPRIM domain and subdomain IV. The catalytic
tyrosine on which the trans-esterification reaction relies is located in
subdomain III. It introduces a nucleophilic attack on a phosphate group of the
nucleotide chain, creating a transient phosphodiester bond with the broken DNA
strand [1,2,3,4,5,6].
There are a number of conserved residues in the region around the active site
tyrosine; we used this region as a signature pattern. We also developed a
profile for the Topo IA-type catalytic domain that covers subdomains II to IV.
-Consensus pattern: [EQ]-x-L-Y-[DEQSTLM]-x(3,12)-[LIVST]-[ST]-Y-x-R-[ST]-
[DEQSN]
[The second Y is the active site tyrosine]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in Swiss-Prot: One, mitochondrial Serine--tRNA
ligase from Fission yeast.
-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: September 2023 / Text revised; profile added.
[ 1] Forterre P., Gribaldo S., Gadelle D., Serre M.-C.
"Origin and evolution of DNA topoisomerases."
Biochimie 89:427-446(2007).
PubMed=17293019; DOI=10.1016/j.biochi.2006.12.009
[ 2] Duguet M., Serre M.-C., Bouthier de La Tour C.
"A universal type IA topoisomerase fold."
J. Mol. Biol. 359:805-812(2006).
PubMed=16647715; DOI=10.1016/j.jmb.2006.04.021
[ 3] Viard T., Bouthier de La Tour C.
"Type IA topoisomerases: a simple puzzle?"
Biochimie 89:456-467(2007).
PubMed=17141394; DOI=10.1016/j.biochi.2006.10.013
[ 4] Moreira F., Arenas M., Videira A., Pereira F.
"Molecular Evolution of DNA Topoisomerase III Beta (TOP3B) in
Metazoa."
J. Mol. Evol. 89:384-395(2021).
PubMed=33999213; DOI=10.1007/s00239-021-10011-7
[ 5] Mondragon A., DiGate R.
"The structure of Escherichia coli DNA topoisomerase III."
Structure 7:1373-1383(1999).
PubMed=10574789; DOI=10.1016/s0969-2126(00)80027-1
[ 6] Balana-Fouce R., Alvarez-Velilla R., Fernandez-Prada C.,
Garcia-Estrada C., Reguera R.M.
"Trypanosomatids topoisomerase re-visited. New structural findings and
role in drug discovery."
Int. J. Parasitol. Drugs. Drug. Resist. 4:326-337(2014).
PubMed=25516844; DOI=10.1016/j.ijpddr.2014.07.006
--------------------------------------------------------------------------------
PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and
distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives
(CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html
--------------------------------------------------------------------------------
{END}