A new role for IQ motif proteins in regulating calmodulin function.
IQ motifs are found in diverse families of calmodulin (CaM)-binding proteins. Some of these, like PEP-19 and RC3, are highly abundant in neuronal tissues, but being devoid of catalytic activity, their biological roles are not understood. We hypothesized that these IQ motif proteins might have unique effects on the Ca2+ binding properties of CaM, since they bind to CaM in the presence or absence of Ca2+. Here we show that PEP-19 accelerates by 40 to 50-fold both the slow association and dissociation of Ca2+ from the C-domain of free CaM, and we identify the sites of interaction between CaM and PEP-19 using NMR. Importantly, we demonstrate that PEP-19 can also increase the rate of dissociation of Ca2+ from CaM when bound to intact CaM-dependent protein kinase II. Thus, PEP-19, and presumably similar members of the IQ family of proteins, has the potential to alter the Ca2+-binding dynamics of free CaM and CaM that is bound to other target proteins. Since Ca2+ binding to the C-domain of CaM is the rate-limiting step for activation of CaM-dependent enzymes, the data reveal a new concept of importance in understanding the temporal dynamics of Ca2+-dependent cell signaling.
Putkey
John A
JA
Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas 77030, USA. John.Putkey@uth.tmc.edu
Kleerekoper
Quinn
Q
Gaertner
Tara R
TR
Waxham
M Neal
MN
D020816:Amino Acid Motifs; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D002147:Calmodulin; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C050394:PCP4 protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium