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 ========================================================================== 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."
* RELATED_TOPICS
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# Genes # Dietary_Supplements_and_Minerals #
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# Genetics # Biochemistry_Research # Biotechnology #
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* RELATED_TERMS
o Protein_biosynthesis o DNA o Protein_folding o Gene o
Molecular_biology o Bioluminescence o RNA o Protein_microarray

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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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