A model of Ca(2+)-free calmodulin binding to unconventional myosins reveals how calmodulin acts as a regulatory switch.
BACKGROUND
In contrast to conventional muscle myosins, where two different light chains (LCs) stabilize the elongated regulatory domain (RD) region of the head portion of the molecule, unconventional myosins are a diverse group of motors in which from one to six calmodulin (CaM) subunits are bound tandemly to the RD. In both cases, the heavy chains of the RDs have special sequences called "IQ motifs' to which the LCs or CaM bind. A previously puzzling aspect of certain unconventional myosins is their unusual mode of regulation, where activation of motility occurs at low levels of Ca2+. Although the atomic structure of the conventional muscle myosin RD has been determined, no crystallographic structure of the RD of an unconventional myosin is yet available.


RESULTS
We have constructed a model of vertebrate CaM bound to the first IQ motif present in the neck region of an unconventional myosin (chicken brush border myosin I), using strict binding rules derived from the crystal structure of the scallop RD. The model accounts for aspects of the regulation of many unconventional myosins where CaM is bound at low levels of Ca2+ and released or changed in conformation at high levels of Ca2+. The conformational changes as a function of Ca2+ depend not only on the precise sequence of the IQ motifs but also on the interactions between CaM molecules bound to adjacent sites on the myosin heavy chain.


CONCLUSIONS
According to our model, the full versatility of CaM binding to target peptides is displayed in the regulation of unconventional myosins. At low concentrations of Ca2+, CaM binds in a manner similar to the LCs of conventional myosins. At higher Ca2+ concentrations, CaM changes conformation and acts as a switch to regulate the activity of the unconventional myosin molecules.
Houdusse
A
A
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02254-9110, USA.
Silver
M
M
Cohen
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000378:metabolism; D018994:Myosin Light Chains / Q000737:chemistry / Q000378:metabolism; D009218:Myosins / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D014336:Troponin / Q000737:chemistry
D002147:Calmodulin; D018994:Myosin Light Chains; D014336:Troponin; D018995:Myosin Heavy Chains; D009218:Myosins; D002118:Calcium