{PDOC00116}
{PS00126; PDEASE_I_1}
{PS51845; PDEASE_I_2}
{BEGIN}
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* 3'5'-cyclic nucleotide phosphodiesterase domain signature and profile *
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3'5'-cyclic nucleotide  phosphodiesterases  (EC 3.1.4.17) (PDEases) comprise a
family of enzymes that modulate the immune response, inflammation, and memory,
among many   other   functions.   They   catalyze  the  hydrolysis  of  cyclic
nucleotides, cAMP  and cGMP, to the corresponding nucleoside 5' monophosphates
[1,2]. There are at least seven different subfamilies of PDEases [3,E1]:

 - Type 1, calmodulin/calcium-dependent PDEases.
 - Type 2, cGMP-stimulated PDEases.
 - Type 3, cGMP-inhibited PDEases.
 - Type 4, cAMP-specific PDEases.
 - Type 5, cGMP-specific PDEases.
 - Type 6, rhodopsin-sensitive cGMP-specific PDEases.
 - Type 7, High affinity cAMP-specific PDEases.

All of these forms contain a catalytic domain of approximately 270 amino acids
at the carboxyl terminus. Regulatory domains that vary widely among the PDEase
subfamilies flank  the catalytic core and include regions that autoinhibit the
catalytic domains  as  well  as  targeting  sequences that control subcellular
localization [2].

The PDEase   catalytic   domains   adopt  a  compact  alpha-helical  structure
consisting of  16 alpha-helices that can be divided into three subdomains (see
<PDB:1F0J>). The  active  site  of PDEases is a deep pocket formed by the tree
subdomains and  can  be  divided  into  two  major  subpockets  for binding of
divalent metals and substrate/inhibitors, respectively. The active site of all
PDEase domains  contains  two divalent metal ions: zinc and probably magnesium
[2,4,5].

We have  derived  a  signature  pattern  from  a  stretch  of 12 residues that
contains two conserved histidines. We also developed a profile that covers the
whole PDEase catalytic domain.

-Consensus pattern: H-D-[LIVMFY]-x-H-x-[AG]-x(2)-[NQ]-x-[LIVMFY]
-Sequences known to belong to this class detected by the pattern: ALL,  except
 Drosophila melanogaster Pde8.
-Other sequence(s) detected in Swiss-Prot:   Bradyrhizobium     diazoefficiens
 dnaE2.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Note: Slime mold extracellular PDEase  and  yeast  low-affinity  PDEase (gene
 PDE1) do not show any similarity with the above enzymes and belong to another
 class of PDEases (see <PDOC00530>).

-Last update: October 2017 / Text revised; profile added.

[ 1] Charbonneau H., Beier N., Walsh K.A., Beavo J.A.
     "Identification of a conserved domain among cyclic nucleotide
     phosphodiesterases from diverse species."
     Proc. Natl. Acad. Sci. U.S.A. 83:9308-9312(1986).
     PubMed=3025833
[ 2] Zhang K.Y.J., Card G.L., Suzuki Y., Artis D.R., Fong D., Gillette S.,
     Hsieh D., Neiman J., West B.L., Zhang C., Milburn M.V., Kim S.-H.,
     Schlessinger J., Bollag G.
     "A glutamine switch mechanism for nucleotide selectivity by
     phosphodiesterases."
     Mol. Cell 15:279-286(2004).
     PubMed=15260978; DOI=10.1016/j.molcel.2004.07.005
[ 3] Beavo J.A., Reifsnyder D.H.
     "Primary sequence of cyclic nucleotide phosphodiesterase isozymes and
     the design of selective inhibitors."
     Trends Pharmacol. Sci. 11:150-155(1990).
     PubMed=2159198
[ 4] Xu R.X., Hassell A.M., Vanderwall D., Lambert M.H., Holmes W.D.,
     Luther M.A., Rocque W.J., Milburn M.V., Zhao Y., Ke H., Nolte R.T.
     "Atomic structure of PDE4: insights into phosphodiesterase mechanism
     and specificity."
     Science 288:1822-1825(2000).
     PubMed=10846163
[ 5] Ke H., Wang H.
     "Crystal structures of phosphodiesterases and implications on
     substrate specificity and inhibitor selectivity."
     Curr. Top. Med. Chem. 7:391-403(2007).
     PubMed=17305581
[E1] http://depts.washington.edu/pde/

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{END}