Structure of mRNA initiation complex could give insight into cancer and
other diseases

Date:
September 3, 2020
Source:
University of California - Davis
Summary:
Researchers have solved the the structure of the complex formed when
mRNA is being scanned to find the starting point for translating
RNA into a protein. The discovery provides a new understanding of
this fundamental process.



FULL STORY ========================================================================== Researchers at the University of California, Davis and the MRC Laboratory
of Molecular Biology in Cambridge, U.K. have solved the the structure of
the complex formed when mRNA is being scanned to find the starting point
for translating RNA into a protein. The discovery, published Sept. 4 in Science, provides new understanding of this fundamental process.


========================================================================== "This structure transforms what we know about translation initiation in
human cells and there has been a tremendous excitement from people in
the field," said Christopher Fraser, professor of molecular and cellular biology at UC Davis and corresponding author on the paper.

Although nearly all our cells contain our entire genome, cells use
different subsets of genes to make the proteins they need to perform
their various functions. This requires precise control over the processes
by which the DNA is first transcribed to produce mRNA and then mRNA is translated to make protein.

ranslation begins when a ribosome attaches to a piece of mRNA and scans
along it until it finds a start codon, three letters of RNA that say
"start translating here." There are over a dozen different proteins known
as initiation factors involved in this process. Many of these initiation factors have been found to be dysregulated in various cancers.

However, just how the factors come together and scan mRNA has been poorly understood, due to the lack of understanding of the structures of the
entire complex.

To investigate this, Fraser and postdoctoral researcher Masaaki
Sokabe at the UC Davis Department of Molecular and Cellular Biology collaborated with Venki Ramakrishnan, Jailson Brito Querido, Sebastian
Kraatz and Yuliya Gordiyenko at the LMB to visualise the structure of
the complex. Ramakrishnan shared the 2009 Nobel Prize for Chemistry for
his work on the structure of the ribosome.

The team used an mRNA that lacked a start codon so that it would be
trapped in the act of scanning. While big for a biological machine,
you could fit about 3000 of these complexes across the width of a human
hair. The team therefore used cryoelectron microscopy at the LMB to obtain
a structure of the complex including the trapped mRNA. Cryoelectron
microscopy allows biologists to capture three-dimensional movies of
biological molecules down to the scale of single atoms.

Based on this structure, the researchers proposed a model of how the mRNA
slots into a channel in the small ribosomal subunit, and a mechanism
for how the mRNA might be pulled through the ribosome for scanning,
like a strip of film through an old-style projector.

They were able to predict that for most mRNAs, the start codon would
need to be sufficiently far from the front end of the mRNA for it to be
found in the scanning process, which was the confirmed biochemically by
Sokabe and Fraser.

Further conformation of the model was obtained by mass spectrometry
carried out by Mark Skehel of the LMB.

The UC Davis College of Biological Sciences recently opened its own cryoelectron microscopy facility, which will make this kind of work
possible on campus, Fraser said.

The work was funded by UKRI MRC, Federation of European Biochemical
Societies, Wellcome, Louis-Jeantet Foundation, and the National Institutes
of Health.


========================================================================== Story Source: Materials provided by
University_of_California_-_Davis. Original written by Andy Fell. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jailson Brito Querido, Masaaki Sokabe, Sebastian Kraatz, Yuliya
Gordiyenko, J. Mark Skehel, Christopher S. Fraser, V. Ramakrishnan.

Structure of a human 48S translational initiation complex. Science,
2020 DOI: 10.1126/science.aba4904 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200903145025.htm

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