NDLI: Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability and lead to cross-β aggregates

Content Provider	PubMed Central
Author	Singh, Surinder M. Kongari, Narsimulu Javier, Cabello-villegas Mallela, Krishna M. G.
Abstract	A deficiency of functional dystrophin protein in muscle cells causes muscular dystrophy (MD). More than 50% of missense mutations that trigger the disease occur in the N-terminal actin binding domain (N-ABD or ABD1). We examined the effect of four disease-causing mutations—L54R, A168D, A171P, and Y231N—on the structural and biophysical properties of isolated N-ABD. Our results indicate that N-ABD is a monomeric, well-folded α-helical protein in solution, as is evident from its α-helical circular dichroism spectrum, blue shift of the native state tryptophan fluorescence, well-dispersed amide crosspeaks in 2D NMR 15N-1H HSQC fingerprint region, and rotational correlation time calculated from NMR longitudinal (T1) and transverse (T2) relaxation experiments. Compared to WT, three mutants—L54R, A168D, and A171P—show a decreased α-helicity and do not show a cooperative sigmoidal melt with temperature, indicating that these mutations exist in a wide range of conformations or in a “molten globule” state. In contrast, Y231N has an α-helical content similar to WT and shows a cooperative sigmoidal temperature melt but with a decreased stability. All four mutants experience serious misfolding and aggregation. FT-IR, circular dichroism, increase in thioflavin T fluorescence, and the congo red spectral shift and birefringence show that these aggregates contain intermolecular cross-β structure similar to that found in amyloid diseases. These results indicate that disease-causing mutants affect N-ABD structure by decreasing its thermodynamic stability and increasing its misfolding, thereby decreasing the net functional dystrophin concentration.
Related Links	http://dx.doi.org/10.1073/pnas.1008818107
Ending Page	15074
Page Count	6
Starting Page	15069
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	34
Volume Number	107
Language	English
Publisher	National Academy of Sciences
Publisher Date	2010-08-24
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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