MSGID: 1:317/3 64b0cf8f   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Structural biology: Molecular scissors caught in the act    
    Structure of an enzyme crucial for tRNA maturation sheds light on cause   
   of neurodegenerative disorders    
      
     Date:   
         July 13, 2023   
     Source:   
         Goethe University Frankfurt   
     Summary:   
         In all living organisms, the biomolecule transfer RNA (tRNA) plays   
         a fundamental role in protein production. tRNAs are generated from   
         precursor molecules in several steps. The enzyme tRNA splicing   
         endonuclease (TSEN), among other things, catalyzes one step in this   
         process. Mutations in TSEN lead to a neurodegenerative disorder   
         called pontocerebellar hypoplasia, which is associated with severe   
         disabilities and early death. Researchers have now deduced the   
         function of TSEN from its structure and in so doing paved the way in   
         the search for active substances against pontocerebellar hypoplasia.   
      
      
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   FULL STORY   
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   Transfer RNAs (tRNAs) are among the most common types of RNA in a cell and   
   are indispensable for protein production in all known organisms. They have   
   an important "translation" function: They determine how the sequence of   
   nucleic acids, in which the genetic information is encoded, is transcribed   
   into a sequence of amino acids from which proteins are built.   
      
   Transfer RNAs are generated from precursor tRNAs (pre-tRNAs), which are   
   converted in several steps into the mature tRNA with a complex three-   
   dimensional structure. In some tRNAs, this includes a step in which a   
   certain section, known as an intron, is excised. In humans, the tRNA   
   splicing endonuclease (TSEN) performs this task.   
      
   The enzyme RNA kinase CLP1, which binds directly to TSEN, also plays a   
   role in ensuring the correct conversion of tRNAs. If TSEN and CLP1 are   
   unable to interact with each other due to a genetic mutation, it seems   
   that tRNAs can no longer form correctly either. The consequences of this   
   are often seen in the development of neurodegenerative disorders. One of   
   these is pontocerebellar hypoplasia, which leads to severe disabilities   
   and premature death in earliest childhood. This very rare progressive   
   disorder manifests itself in an abnormal development of the cerebellum   
   and the pons, a part of the brain stem.   
      
   Although TSEN activity is essential for life, it was to date mostly   
   unclear how the enzyme binds pre-tRNAs and how introns are excised. The   
   lack of a three- dimensional structure of the enzyme also made it   
   difficult to assess the changes triggered by specific pathogenic   
   mutations. By means of cryo-electron microscopy (cryo-EM) conducted at   
   facilities of the Julius-Maximilians University of Wu"rzburg and of the   
   Institute of Biochemistry at Goethe University Frankfurt, researchers   
   led by Dr. Simon Trowitzsch from the Institute of Biochemistry at Goethe   
   University have now succeeded in shedding light on the three-dimensional   
   structure of a TSEN/pre-tRNA complex.   
      
   With the aid of their cryo-EM reconstructions, the research team was   
   able to show for the first time how TSEN interacts with the L-shaped   
   pre-tRNA. TSEN then excises the intron from the long arm of the L. "First,   
   TSEN settles in the corner of the L. It can then recognize both the short   
   and the long arm as well as the angle between them," explains Trowitzsch.   
      
   The TSEN subunit 54 (TSEN54) plays a key role in pre-tRNA recognition,   
   as the researchers have now been able to corroborate. The subunit serves   
   as a "molecular ruler" and measures the distance between the long and   
   the short arm of the L. In this way, TSEN recognizes at which point the   
   pre-tRNA needs to be cleaved in order to remove the intron.   
      
   New findings on the interaction of the RNA kinase CLP1 and the TSEN   
   subunit TSEN54 were a surprise: CLP1 evidently binds to an unstructured   
   and thus very flexible region of TSEN54. It is precisely this region   
   that contains an amino acid most frequently mutated in patients with   
   pontocerebellar hypoplasia. "For us, this is an important indication   
   that drug development in the future should concentrate on maintaining   
   the interaction of TSEN and CLP1," Samoil Sekulovski, first author of   
   the study, is convinced.   
      
   The scientists now hope that the structural data will make it possible   
   to simulate models that can be used to search for potential active   
   substances.   
      
   Trowitzsch sums up: "Although a promising therapy is still a long way   
   ahead of us, our structure indeed forms a solid foundation for a better   
   understanding of how TSEN works and what the disease patterns of its   
   mutants are."   
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   Materials provided by Goethe_University_Frankfurt. Note: Content may be   
   edited for style and length.   
      
      
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   Journal Reference:   
      1. Samoil Sekulovski, Lukas Susac, Lukas S. Stelzl, Robert Tampe',   
      Simon   
         Trowitzsch. Structural basis of substrate recognition by human tRNA   
         splicing endonuclease TSEN. Nature Structural & Molecular Biology,   
         2023; 30 (6): 834 DOI: 10.1038/s41594-023-00992-y   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230713142016.htm   
      
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