Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C1762617 (weakness)
37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E41K mutation in TPM2 gene encoding muscle regulatory protein beta-tropomyosin is associated with nemaline myopathy and cap disease. The mutation results in a reduced Ca²⁺-sensitivity of the thin filaments and in muscle weakness. To elucidate the structural basis of the reduced Ca²⁺-sensitivity of the thin filaments, we studied multistep changes in spatial arrangement of tropomyosin (Tpm), actin and myosin heads during the ATPase cycle in reconstituted fibers, using the polarized fluorescence microscopy. The E41K mutation inhibits troponin's ability to shift Tpm to the closed position at high Ca²⁺, thus restraining the transition of the thin filaments from the "off" to the "on" state. The mutation also inhibits the ability of S1 to shift Tpm to the open position, decreases the amount of the myosin heads bound strongly to actin at high Ca²⁺, but increases the number of such heads at low Ca²⁺. These changes may contribute to the low Ca²⁺-sensitivity and muscle weakness. As the mutation has no effect on troponin's ability to switch actin monomers on at high Ca²⁺ and inhibits their switching off at low Ca²⁺, the use of reagents that increase the Ca²⁺-sensitivity of the troponin complex may not be appropriate to restore muscle function in patients with this mutation.
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PMID:The reason for the low Ca²⁺-sensitivity of thin filaments associated with the Glu41Lys mutation in the TPM2 gene is "freezing" of tropomyosin near the outer domain of actin and inhibition of actin monomer switching off during the ATPase cycle. 2979 62


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