The Impairment of TorsinA's Binding to and Interactions With Its Activator: An Atomistic Molecular Dynamics Study of Primary Dystonia.

ABSTRACT: Primary dystonia's prolonged muscle contractions and the associated abnormal postures and twisting movements remain incurable. Genetic mutation/deletion of GAG from TorsonA's gene resulting in ?E303 (which weakens the binding between TorsinA and its activator, such as LULL1) primarily cause this neurodegenerative disorder. We studied TorsinA-LULL1 (or TorsinA?E303-LULL1) bindings and interactions. For the first time, we show the atomic details of TorsinA-LULL1 dynamic interactions and TorsinA?E303-LULL1 dynamic interactions and their binding affinities. Our results show extensive effects of ?E303 on TorsinA?E303-LULL1 interactions, and suggest that the differences between TorsinA-LULL1 interactions and TorsinA?E303-LULL1 interactions are non-subtle. ?E303 significantly weakens TorsinA?E303-LULL1's binding affinity. We present pieces of evidence proving that the effects of ?E303 (on the differences between TorsinA-LULL1 interactions and TorsinA?E303-LULL1 interactions) are more pronounced than previously suggested, and that the nanobody used for achieving the X-ray crystallization in the previous study attenuated the differences between TorsinA-LULL1 and TorsinA?E303-LULL1 interactions. Our accounts of the dynamic interactions between "TorsinA and LULL1" and between "TorsinA?E303 and LULL1" and the detailed effects of ?E303 on TorsinA-/TorsinA?E303-LULL1 build on previous findings and offer new insights for a better understanding of the molecular basis of Primary Dystonia. Our results have long-term potentials of guiding the development of medications for the disease.

SUBMITTER: Salawu EO 

PROVIDER: S-EPMC6048259 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature