Scientists from the
Florida campus of The Scripps Research Institute have identified a series of
intricate biochemical steps that lead to the successful production of proteins,
the basic working units of any cell.
The study, which appears in the July 6, 2012 edition of
the journal Cell, sheds light on the assembly of a structure called
the ribosome, a large and
complex protein-producing machine
inside all living cells.
Ribosomes are the targets of many commercially used antibiotics and represent a
promising area of research because of the importance of ribosome assembly and
function for cell growth. There are well-established links between defects in
ribosome assembly and cancer, making this pathway a potential new target
for anti-cancer drugs.
"With important cellular machines like ribosomes, it
makes sense that some process exists to make sure things work correctly,"
said Katrin Karbstein, a Scripps Research associate professor who led the
study. "We've shown that such a quality control function
exists for ribosomal subunits that use the system to do a test run but don't
produce a protein. If the subunits don't pass, there are mechanisms to discard
them."
Protein Production Line
As part of the protein-production process
called "translation," the ribosome decodes information carried in
messenger RNA (mRNA) to produce a protein—a chain of amino acids.
To produce mature, functioning ribosomal RNAs (rRNAs),
the body first makes precursor rRNAs that can be processed into mature ones. In
human cells, this is done in two stages—the first occurs in the nucleolus, a
protein-nucleic acid structure inside the nucleus, and finally in the
cytoplasm, the basic cellular stew where protein translation occurs.
In the cytoplasm, these pre-mature ribosomal subunits
encounter large pools of mature subunits, messenger RNA, and numerous assembly
factors and translation factors that help complete the process.
During the final maturation process, various assembly
factors prevent the translation process from acting on the subunits
prematurely, which would result in their rapid degradation or in the production
of incorrectly assembled proteins, both processes with potentially lethal
outcomes for the cell.
Trial Run
While the work of these assembly factors explains how
premature translation is blocked, their presence raises another important
question, Karbstein said—Does the conversion of inactive assembly intermediates
into mature ribosomes require checkpoints to assure that subunits are
functional?
In the study, Karbstein and her colleagues were able to
show that during this translation-like cycle the newly made ribosome subunit
initially joins with its complementary preexisting subunit to form a much larger
complex through the influence of a single translation factor.
This large ribosome complex contains no messenger RNA, which is blocked
by assembly factors, and thus produces no protein. Once the major functions of
the smaller ribosome subunit have been inspected and approved, another
translation factor breaks up the complex and actual protein production occurs.
"What is important here is that the test cycle
involves the same translational factors that are involved in normal
translation," Karbstein said. "It's the most elegant and efficient
way to produce perfect ribosomes."
Interestingly, the study noted, the majority of assembly
factors involved in this translation-like test cycle are conserved in creatures
ranging from one-celled organisms to humans, suggesting that this
evolutionary mechanism is
common to all.
More information: "Joining
of 60S Subunits and a Translation-like Cycle in 40S Ribosome Maturation" Cell,
2012.
Provided by Scripps Research
Institute
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