Structural interactions between actin, tropomyosin, caldesmon and calcium binding protein and the regulation of smooth muscle thin filaments.
The basic structure and functional properties of smooth muscle thin filaments were established about 10 years ago. Since then we and others have been working on the details of how tropomyosin, caldesmon and the Ca(2+)-binding protein regulate actin interaction with myosin. Our work has tended to emphasize the similarities between caldesmon and troponin function whilst others have been more concerned with the differences. The need to resolve the resulting differences has stimulated us to find new and more direct ways of investigating the mechanism of thin filament regulation. In recent years an apparent divergence has opened up between functional measurements, which indicate an allosteric-cooperative regulatory mechanism in which caldesmon and Ca(2+)-binding protein control actin-tropomyosin state in the same way as troponin, and structural measurements which show thin filament structures unlike striated muscle thin filaments. The challenge is to interpret function in terms of structure. We have combined functional studies with expression and mutagenesis of caldesmon and with structural methods including X-ray crystalography of tropomyosin-caldesmon crystals, electron microscopy and helical reconstruction of actin-tropomyosin-caldesmon complexes and high resolution nuclear magnetic resonance spectroscopy of the C-terminus of caldesmon in interaction with actin and calmodulin. We have used this information to propose a structural mechanism for caldesmon regulation of the smooth muscle thin filament.
Marston
S
S
Imperial College School of Medicine, National Heart and Lung Institute, London, UK.
Burton
D
D
Copeland
O
O
Fraser
I
I
Gao
Y
Y
Hodgkinson
J
J
Huber
P
P
Levine
B
B
el-Mezgueldi
M
M
Notarianni
G
G
D000199:Actins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism / Q000502:physiology*; D014335:Tropomyosin / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D014335:Tropomyosin