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Conformational dynamics inside amino-terminal disease hotspot of ryanodine receptor.

ABSTRACT: The N-terminal region of both skeletal and cardiac ryanodine receptor is a disease mutation hotspot. Recently, a crystal structure of the RyR1 fragment (residues 1-559) was solved. This N-terminal structure contains three separate domains, A, B, and C, and was docked into a central vestibule in a full-length RyR1 cryo-EM map. Here, we reconstructed three-dimensional cryo-EM structures of two GFP-tagged RyR2s with GFP inserted after residue Glu-310 and Ser-437, respectively. The structures of RyR2E310-GFP and RyR2S437-GFP displayed an extra mass on domain B and C, directly validating the predicted docking model. Next, we revealed domain movements in molecular dynamics flexible fitting models in both the closed and open state cryo-EM maps. To further probe the conformational changes, we generated FRET pairs by inserting CFP or YFP in two selected domains, FRET studies of three dual-insertion pairs and three co-expressed single-insertion pairs showed the dynamic structural changes within the N-terminal domains.

SUBMITTER: Zhong X 

PROVIDER: S-EPMC3826818 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Conformational dynamics inside amino-terminal disease hotspot of ryanodine receptor.

Zhong Xiaowei X   Liu Ying Y   Zhu Li L   Meng Xing X   Wang Ruiwu R   Van Petegem Filip F   Wagenknecht Terence T   Chen S R Wayne SR   Liu Zheng Z  

Structure (London, England : 1993) 20131017 11

The N-terminal region of both skeletal and cardiac ryanodine receptor is a disease mutation hotspot. Recently, a crystal structure of the RyR1 fragment (residues 1-559) was solved. This N-terminal structure contains three separate domains, A, B, and C, and was docked into a central vestibule in a full-length RyR1 cryo-EM map. Here, we reconstructed three-dimensional cryo-EM structures of two GFP-tagged RyR2s with GFP inserted after residue Glu-310 and Ser-437, respectively. The structures of RyR  ...[more]

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