The reason for a high Ca2+-sensitivity associated with Arg91Gly substitution in TPM2 gene is the abnormal behavior and high flexibility of tropomyosin during the ATPase cycle
- Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Avenue, St. Petersburg 194064 (Russian Federation)
- Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU (United Kingdom)
Highlights: • Mutation R91G initiates abnormally high flexibility of β-tropomyosin (TM). • Troponin moves R91G-TM to the blocked position at low Ca{sup 2+}. • This mutation does not alter the ability of troponin to switch off actin monomers. • R91G-TM is located near the open position during the ATPase cycle at low Ca{sup 2+}. • Mutation R91G increases the fraction of rigor myosin heads at low Ca{sup 2+}. Substitution of Arg for Gly residue in 91th position in β-tropomyosin caused by a point mutation in TPM2 gene is associated with distal arthrogryposis, characterized by a high Ca{sup 2+}-sensitivity of myofilament and contracture syndrome. To understand the mechanisms of this defect, we studied multistep changes in mobility and spatial arrangement of tropomyosin, actin and myosin heads during the ATPase cycle in reconstituted ghost fibres, using the polarized fluorescence microscopy. The mutation was shown to markedly decrease the bending stiffness of β-tropomyosin in the thin filaments. In the absence of the myosin heads the mutation did not alter the ability of troponin to shift tropomyosin to the blocked position and to switch actin monomers off at low Ca{sup 2+}. During the ATPase cycle the movement of the mutant tropomyosin is restrained, it is located near the open position, which allows strong binding of the myosin heads to actin even at low Ca{sup 2+}. This may be the reason for both high Ca{sup 2+}-sensitivity and contractures associated with the Arg91Gly mutation. The use of reagents that decrease the Ca{sup 2+}sensitivity of the troponin complex may not be appropriate to restore muscle function in patients with this mutation.
- OSTI ID:
- 22897523
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 3-4 Vol. 494; ISSN BBRCA9; ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Reverse actin sliding triggers strong myosin binding that moves tropomyosin
The flexibility of two tropomyosin mutants, D175N and E180G, that cause hypertrophic cardiomyopathy