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Multitasking secrets of RNA-binding

There are hundreds of RNA-binding proteins in an entire human genome. They regulate turnover and fixing in place of many thousands of RNA molecules within cells. They are crucial in maintaining normal cell function. Any defects in RNA-binding proteins can lead to disease.


For example, RNA-binding proteins are overexpressed in many human cancers. Mutations in some are linked to neurologic and neurodegenerative disorders such as ALS — amyotrophic lateral sclerosis. "Understanding the fundamental properties of this class of proteins is very relevant," says Elizabeth Gavis, the Damon B. Pfeiffer PhD, professor of Molecular Biology and Director of Undergraduate Studies in the department of Molecular Biology at Princeton University.


RNA-binding proteins also control
the translation of RNA into proteins.


Researchers from Princeton University and the National Institute of Environmental Health Sciences have now discovered how a fruit fly protein binds and regulates two different types of RNA sequences. The study, published in the journal Cell Reports, helps explain how various RNA-binding proteins are able to perform so many different functions within a cell.

Gavis and her colleagues followed a protein called Glorund (Glo), an RNA-binding protein that functions during fruit fly development. Glo was originally identified by its ability to repress translation of an RNA molecule called Nanos into a protein found in fly eggs. In the process of translation, messenger RNA (mRNA) is decoded by a ribosome, a structure existing outside the nucleus of a cell, in order to produce a specific amino acid chain — a polypeptide. A polypeptide chain is made up of a large number of amino-acid residues all bound together into a chain to form part, or the entire protein molecule. That molecule later must fold to become an active protein that can function within a cell. A stable pairing must occur between the 4 different elements making up the rungs of DNA — between guanine and cytosine, adenine and thymine. But in RNA, the pairing is between adenine and uracil. By binding to a Nanos RNA structure made up of uracil and adenine, Glo prevents production of the Nanos protein normally found at the front of the embryo, enabling the fly's head to form.

Glo, like many other RNA-binding proteins, is multifunctional. It regulates several steps in fly development by binding to RNAs other than Nanos. The mammalian counterparts of Glo — known as heterogeneous nuclear ribonucleoprotein (hnRNP) F/H proteins — bind to RNAs containing stretches of guanine nucleotides known as G-tracts, and rather than repressing translation, mammalian hnRNP F/H proteins regulate processes such as RNA splicing, in which RNAs are rearranged to produce alternative versions of proteins they encode.

To understand how Glo might bind to diverse RNAs and regulate them in different ways, Gavis and graduate student Joel Tamayo collaborated with Traci Tanaka Hall and Takamasa Teramoto from the National Institute of Environmental Health Sciences to generate X-ray crystallographic structures of Glo's three RNA-binding domains. As expected, the three domains were almost identical to the corresponding domains of mammalian hnRNP F/H proteins. For example, they retained the amino acid residues that bind to G-tract RNA, researchers confirmed that, like their mammalian counterparts, each RNA-binding domain of Glo can bind to this type of RNA sequence. However, the researchers also saw something new.

"When we looked at the structures, we realized there were also some basic amino acids that projected from a different part of the RNA-binding domains that could be involved in contacting RNA,"
Gavis explained. These basic amino acids mediate binding to uracil-adenine (U-A) stem structures like the one found in Nanos RNA. Each of Glo's RNA-binding domains therefore contains two distinct binding surfaces that interact with different types of RNA target sequence. "While there have been examples previously of RNA-binding proteins that carry more than one binding domain, each with a different specificity, this represents the first example of a single domain harboring two different specificities," said Howard Lipshitz, a professor of molecular genetics at the University of Toronto who was not involved in the study.

To investigate which of Glo's two RNA-binding modes was required for its different functions in flies, Gavis and colleagues generated insects carrying mutant versions of the RNA-binding protein. Glo's ability to repress nanos translation during egg development required both of the protein's RNA-binding modes. The researchers discovered that, as well as binding the U-A stem in the nanos RNA, Glo also recognized a nearby G-tract sequence. But Glo's ability to regulate other RNAs at different developmental stages only depended on the protein's capacity to bind G-tracts.

"We think that the binding mode may correlate with Glo's activity towards a particular RNA," said Gavis. "If it binds to a G-tract, Glo might promote RNA splicing. If it simultaneously binds to both a G-tract and a U-A stem, Glo acts as a translational repressor."


RNA-binding domains of mammalian hnRNP F/H proteins probably have a similar ability to bind two different types of RNA, allowing them to regulate diverse target RNAs within the cell.


"This paper represents an exciting advance in a field that has become increasingly important with the discovery that defects in RNA-binding proteins contribute to human diseases such as metabolic disorders, cancer and neurodegeneration," Lipshitz adds. "As these proteins are evolutionarily conserved from fruit flies to humans, experiments of this type tell us a lot about how their human versions normally work or can go wrong."

Highlights
•Glorund binds G-tract and structured UA-rich RNAs using different qRRM interfaces
•Translational repression of nanos mRNA requires both Glorund RNA recognition modes
•Regulation of some Glorund targets in vivo requires only G-tract binding
•Diversification of RNA recognition may expand the functional repertoire of an RBP

Summary
The Drosophila hnRNP F/H homolog, Glorund (Glo), regulates nanos mRNA translation by interacting with a structured UA-rich motif in the nanos 3′ untranslated region. Glo regulates additional RNAs, however, and mammalian homologs bind G-tract sequences to regulate alternative splicing, suggesting that Glo also recognizes G-tract RNA. To gain insight into how Glo recognizes both structured UA-rich and G-tract RNAs, we used mutational analysis guided by crystal structures of Glo’s RNA-binding domains and identified two discrete RNA-binding surfaces that allow Glo to recognize both RNA motifs. By engineering Glo variants that favor a single RNA-binding mode, we show that a subset of Glo’s functions in vivo is mediated solely by the G-tract binding mode, whereas regulation of nanos requires both recognition modes. Our findings suggest a molecular mechanism for the evolution of dual RNA motif recognition in Glo that may be applied to understanding the functional diversity of other RNA-binding proteins.

Keywords:
Glorund, nanos, Drosophila, hnRNP, hnRNP F, hnRNP H, RNA-binding protein, translational control, translational repressor, post-transcriptional regulation, development
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Apr 13, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



Two views of one of Glo's RNA-binding domains highlight the amino acids
required for binding G-tract RNA (left) and U-A stem structures (right).
Image Credit:
Cell Reports

 


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