{PDOC52082}
{PS52082; 5_PPASE}
{BEGIN}
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* 5-phosphatase (5-PPase) domain profile *
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Phosphoinositides (PIPs)   are  membrane  lipids  that,  together  with  their
corresponding soluble  inositol  phosphates  (IPs),  regulate various cellular
processes, including  membrane  recruitment of proteins, actin polymerization,
synaptic vesicle  trafficking and exo- and endocytosis. The dynamic control of
the membrane  distribution  and  relative  abundance  of  the  seven naturally
occurring PIPs  by  a  multitude  of phosphoinositide kinases and phosphatases
forms a  versatile  signaling  mechanism able to tune the spatial and temporal
regulation of many crucial events in the cell.

The inositol  polyphosphate 5-phosphatases (5-phosphatases or 5-PPases) form a
family of  Mg(2+)-dependent  enzymes,  containing ten members in mammals, that
catalyse the  hydrolytic  removal  of the phosphate group on the 5-position of
lipid-bound and soluble inositol phosphates. This family comprises ten members
in mammals  that  share the catalytic 5-PPase domain. Based on their substrate
specificity, the  mammalian  5-PPases  can  be  further  subdivided  into four
groups: the  type  I 5-PPase INPP5A, the type II 5-PPases OCRL, INPP5B, INPP5J
(or PIPP),  SKIP,  Synaptojanin1  (Synj1) and Synaptojanin 2 (Synj2), the type
III 5-PPases,  SHIP1  and  SHIP2, and the type IV 5-PPase INPP5E (or Pharbin).
These members  share  a catalytic 5-PPase domain with a set of conserved amino
acids.

The 5-PPase  domain is composed of two antiparallel beta-sheets forming a beta
sandwich surrounded  by several alpha-helices (see <PDB:7A0V>). The substrates
bind to one terminus of the beta-sandwich where the substrate interactions are
made by  several  loops and short helices connecting the beta-strands. The 1-P
group of  the  substrate  constitutes,  together  with  the inositol ring, the
conserved polar  moiety  of all phosphoinositide substrates and is expected to
be a  key  unit for substrate recognition. A tentative catalytic Mg(2+) ion is
found in  the  active  site. The 5-P binds in a pocket containing six residues
that are  highly  conserved  in the 5-phosphatases (a Lys, an Asp, two Asn and
two His).  At  this  position, the 5-P interacts directly with Mg(2+) and also
makes direct  contacts  with  the  two  His,  one of the Asn, and the Asp. The
catalytic Asp acts  as  a base, deprotonating a bound water molecule to form a
hydroxide ion. The hydroxide attacks the phosphorus atom of the 5-P, forming a
pentavalent transition  state.  The  highly negatively charged intermediate is
stabilized by  the  Mg(2+),  which  is  coordinated  by invariable Glu and Asn
residues. The  bond  between  the  phosphate  and the inositol ring is broken,
releasing inorganic phosphate (Pi) [1,2,3,4,5,6].

The profile we developed covers the entire 5-PPase domain.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: November 2025 / First entry.

[ 1] Paesmans J., Martin E., Deckers B., Berghmans M., Sethi R., Loeys Y.,
     Pardon E., Steyaert J., Verstreken P., Galicia C., Versees W.
     "A structure of substrate-bound Synaptojanin1 provides new insights in
     its  mechanism and the effect of disease mutations."
     Elife 9:0-0(2020).
     PubMed=33349335; DOI=10.7554/eLife.64922
[ 2] Martin E., Giakoumakis D., Paesmans J., Bisi N., Drozdzecki A.,
     Audenaert D., Haustraete J., Verstreken P., Galicia C., Ballet S.,
     Versees W.
     "Discovery and Characterization of a Selective Inhibitor of
     Synaptojanin1  5-Phosphatase Activity."
     ACS. Pharmacol. Transl. Sci. 8:2996-3006(2025).
     PubMed=40969890; DOI=10.1021/acsptsci.5c00210
[ 3] Mills S.J., Silvander C., Cozier G., Tresaugues L., Nordlund P.,
     Potter B.V.
     "Crystal Structures of Type-II Inositol Polyphosphate 5-Phosphatase
     INPP5B with  Synthetic Inositol Polyphosphate Surrogates Reveal New
     Mechanistic Insights for  the Inositol 5-Phosphatase Family."
     Biochemistry 55:1384-1397(2016).
     PubMed=26854536; DOI=10.1021/acs.biochem.5b00838
[ 4] Schurmans S., Vande Catsyne C.A., Desmet C., Moes B.
     "The phosphoinositide 5-phosphatase INPP5K: From gene structure to in
     vivo  functions."
     Adv. Biol. Regul. 79:100760-100760(2021).
     PubMed=33060052; DOI=10.1016/j.jbior.2020.100760
[ 5] Tresaugues L., Silvander C., Flodin S., Welin M., Nyman T.,
     Graeslund S., Hammarstroem M., Berglund H., Nordlund P.
     "Structural basis for phosphoinositide substrate recognition,
     catalysis, and  membrane interactions in human inositol polyphosphate
     5-phosphatases."
     Structure 22:744-755(2014).
     PubMed=24704254; DOI=10.1016/j.str.2014.01.013
[ 6] Tsujishita Y., Guo S., Stolz L.E., York J.D., Hurley J.H.
     "Specificity determinants in phosphoinositide dephosphorylation:
     crystal structure  of an archetypal inositol polyphosphate
     5-phosphatase."
     Cell 105:379-389(2001).
     PubMed=11348594; DOI=10.1016/s0092-8674(01)00326-9

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