The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.

Dystrophin and utrophin link the F-actin cytoskeleton to the cell membrane via an associated glycoprotein complex. This functionality results from their domain organization having an N-terminal actin-binding domain followed by multiple spectrin-repeat domains and then C-terminal protein-binding moti...

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Autores principales:	Muralidharan Muthu, Kylie A Richardson, Andrew J Sutherland-Smith
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/be27e30badbe48c4aa5a01ec92a60f4a
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spelling	oai:doaj.org-article:be27e30badbe48c4aa5a01ec92a60f4a2021-11-18T07:11:45ZThe crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.1932-620310.1371/journal.pone.0040066https://doaj.org/article/be27e30badbe48c4aa5a01ec92a60f4a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22911693/?tool=EBIhttps://doaj.org/toc/1932-6203Dystrophin and utrophin link the F-actin cytoskeleton to the cell membrane via an associated glycoprotein complex. This functionality results from their domain organization having an N-terminal actin-binding domain followed by multiple spectrin-repeat domains and then C-terminal protein-binding motifs. Therapeutic strategies to replace defective dystrophin with utrophin in patients with Duchenne muscular dystrophy require full-characterization of both these proteins to assess their degree of structural and functional equivalence. Here the high resolution structures of the first spectrin repeats (N-terminal repeat 1) from both dystrophin and utrophin have been determined by x-ray crystallography. The repeat structures both display a three-helix bundle fold very similar to one another and to homologous domains from spectrin, α-actinin and plectin. The utrophin and dystrophin repeat structures reveal the relationship between the structural domain and the canonical spectrin repeat domain sequence motif, showing the compact structural domain of spectrin repeat one to be extended at the C-terminus relative to its previously defined sequence repeat. These structures explain previous in vitro biochemical studies in which extending dystrophin spectrin repeat domain length leads to increased protein stability. Furthermore we show that the first dystrophin and utrophin spectrin repeats have no affinity for F-actin in the absence of other domains.Muralidharan MuthuKylie A RichardsonAndrew J Sutherland-SmithPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e40066 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Muralidharan Muthu Kylie A Richardson Andrew J Sutherland-Smith The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
description	Dystrophin and utrophin link the F-actin cytoskeleton to the cell membrane via an associated glycoprotein complex. This functionality results from their domain organization having an N-terminal actin-binding domain followed by multiple spectrin-repeat domains and then C-terminal protein-binding motifs. Therapeutic strategies to replace defective dystrophin with utrophin in patients with Duchenne muscular dystrophy require full-characterization of both these proteins to assess their degree of structural and functional equivalence. Here the high resolution structures of the first spectrin repeats (N-terminal repeat 1) from both dystrophin and utrophin have been determined by x-ray crystallography. The repeat structures both display a three-helix bundle fold very similar to one another and to homologous domains from spectrin, α-actinin and plectin. The utrophin and dystrophin repeat structures reveal the relationship between the structural domain and the canonical spectrin repeat domain sequence motif, showing the compact structural domain of spectrin repeat one to be extended at the C-terminus relative to its previously defined sequence repeat. These structures explain previous in vitro biochemical studies in which extending dystrophin spectrin repeat domain length leads to increased protein stability. Furthermore we show that the first dystrophin and utrophin spectrin repeats have no affinity for F-actin in the absence of other domains.
format	article
author	Muralidharan Muthu Kylie A Richardson Andrew J Sutherland-Smith
author_facet	Muralidharan Muthu Kylie A Richardson Andrew J Sutherland-Smith
author_sort	Muralidharan Muthu
title	The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
title_short	The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
title_full	The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
title_fullStr	The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
title_full_unstemmed	The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
title_sort	crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/be27e30badbe48c4aa5a01ec92a60f4a
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The crystal structures of dystrophin and utrophin spectrin repeats: implications for domain boundaries.

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