Document Detail


Identification of inhibitory and calmodulin-binding domains of the PDE1A1 and PDE1A2 calmodulin-stimulated cyclic nucleotide phosphodiesterases.
MedLine Citation:
PMID:  8537356     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Using a bovine 61-kDa (PDE1A2) calmodulin-stimulated phosphodiesterase (CaM-PDE) cDNA and a bovine lung 59-kDa (PDE1A1) CaM-PDE cDNA reported here, we have identified two new regions within the primary structure of these two related isozymes that are important for regulation by Ca2+/CaM. PDE1A1 is identical to the PDE1A2 isozyme except for the amino-terminal 18 residues. In agreement with earlier studies, the CaM concentration required for half-maximal activation (KCaM) of recombinant PDE1A1 (0.3 nM) was approximately 10-fold less than the KCaM for recombinant PDE1A2 (4 nM). A series of deletion mutations of the PDE1A2 cDNA removing nucleotide sequence encoding the first 46-106 aminoterminal residues were constructed and expressed using the baculovirus system. Deletion of the amino acids encompassing a previously identified, putative CaM-binding domain (residues 4-46) produced a polypeptide that was still activated 3-fold by CaM (KCaM approximately 3 nM). However, complete CaM-independent activation occurred when residues 4-98 were deleted. To determine the location of the additional CaM-binding domain(s), the inhibitory potency of seven overlapping, synthetic peptides spanning amino acids 76-149 of PDE1A2 was tested using the CaM-activated enzyme. One peptide spanning amino acids 114-137 of PDE1A2 appeared to be the most potent inhibitor of CaM-stimulated activity. These results reveal the existence of a CaM-binding domain located approximately 90 residues carboxyl-terminal to the putative CaM-binding domains previously identified within the PDE1A1 and PDE1A2 isozymes. Moreover, a discrete segment important for holding these CaM-PDEs in a less active state at low Ca2+ concentrations is located between the two CaM-binding domains.
Authors:
W K Sonnenburg; D Seger; K S Kwak; J Huang; H Charbonneau; J A Beavo
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  270     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1995 Dec 
Date Detail:
Created Date:  1996-02-08     Completed Date:  1996-02-08     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  30989-1000     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of Washington, Seattle 98195, USA.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/L34069
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MeSH Terms
Descriptor/Qualifier:
3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors,  genetics,  metabolism*
Amino Acid Sequence
Animals
Base Sequence
Calmodulin / metabolism*
Catalysis
Cattle
Cyclic AMP-Dependent Protein Kinases / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 1
DNA, Complementary
Isoenzymes / antagonists & inhibitors,  metabolism*
Lung / enzymology
Molecular Sequence Data
Phosphoric Diester Hydrolases*
Phosphorylation
Sequence Alignment
Substrate Specificity
Grant Support
ID/Acronym/Agency:
DK21723/DK/NIDDK NIH HHS; HL44948/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Calmodulin; 0/DNA, Complementary; 0/Isoenzymes; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.1.4.-/Phosphoric Diester Hydrolases; EC 3.1.4.17/3',5'-Cyclic-AMP Phosphodiesterases; EC 3.1.4.17/Cyclic Nucleotide Phosphodiesterases, Type 1

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