Structure Shows One Way Body Controls Gene Expression
By Jason Socrates Bardi
A group of scientists at The Scripps Research Institute
has solved the structure of a protein that regulates the expression
of genes by controlling the stability of mRNA—an intermediate
form of genetic information between DNA genes and proteins.
"Gene expression can be controlled at many levels," says
Scripps Research Professor Peter Wright, who is chairman of
the Department of Molecular Biology and Cecil H. and Ida M.
Green Investigator in Medical Research at Scripps Research.
"One of them is at the level of the message."
The structure of the "tandem zinc finger" domain of the
regulatory protein TIS11d in complex with a strand of mRNA
was solved in the laboratory of Wright and H. Jane Dyson,
by Maria A. Martinez-Yamout of Scripps Research, and Brian
P. Hudson, now at Rutgers University. This is the first such
structure to be solved, and it provides insights into the
process of gene regulation at the atomic level.
In next month's issue of Nature Structural & Molecular
Biology, Wright and his colleagues describe the tandem
zinc finger—thus called because it contains two finger-like
domains that must bind to zinc to fold into its active form.
These tandem zinc fingers are a very common motif in mammalian
genes, and hundreds of genes in the human genome contain some
version of them. This diversity is perhaps indicative of the
capability of TZF proteins to specifically recognize a large
number of different RNA sequence motifs.
Insights into the workings of the regulatory protein TIS11d
are particularly valuable because these proteins are involved
in a number of fundamental biological processes, such as inflammation,
and are potential targets for therapeutics in diseases where
these processes go awry.
The Regulation of Genes at the mRNA Level
Regulation of gene expression in humans and other organisms
is a crucial part of biology, and biology has a large repertoire
of mechanisms for turning genes on and off. Many of the proteins
encoded by genes in human and other genomes specialize in
regulating other genes, often in complicated feedback mechanisms.
Shutting off the transcription of a gene—the process
whereby a single-stranded piece of messenger RNA (mRNA) is
made from a double-stranded piece of DNA—has for decades
been recognized by molecular and cell biologists as a crucial
way the cell regulates the expression of a gene.
In the last several years, many of these same scientists,
including Wright and his colleagues, have been growing aware
of the importance of post-transcriptional gene regulation,
which occurs at the level of mRNA.
In mammals, once DNA genes are transcribed into mRNAs in
the nucleus of a cell, they are usually transported outside
the nucleus, where the mRNAs can be "translated" into proteins.
At this point, certain regulatory proteins stabilize the mRNA,
allowing it to be translated by the cell's machinery into
proteins. Other regulatory proteins destabilize the mRNAs,
marking them for degradation by the cell's machinery.
TIS11d belongs to a common family of regulatory proteins
of this latter type. It regulates the levels of many important
proteins involved in the body's inflammatory response, such
as tumor necrosis factor (TNF) and interferons, by marking
the TNF and interferon mRNAs for destruction. With incredible
specificity, this protein uses its tandem zinc finger domain
to recognize particular sequences of TNF and interferon mRNA.
By solving the structure, Wright and his colleagues revealed
for the first time in atomic detail exactly how this recognition
occurs.
The TIS11d protein basically mimics the base-pairing that
takes place in DNA by using its tandem zinc finger domains
to bind to the mRNA. Following the same principle that two
strands of DNA use to bind to each other, the TIS11d protein
binds to the mRNA by forming hydrogen bonds with the Watson-Crick
edges of the mRNA.
"It was remarkable to see how these tiny structures [work],"
says Wright.
The research article "Recognition of the mRNA AU-rich element
by the zinc finger domain of TIS11d" is authored by Brian
P. Hudson, Maria A. Martinez-Yamout, H. Jane Dyson, and Peter
E. Wright and appears in the March 2004 issue of Nature
Structural & Molecular Biology.
The research was funded by the National Institutes of Health
and The Skaggs Institute for Research.
Send comments to: jasonb@scripps.edu
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