Proteins are the workhorses of cells, carrying out a vast array of functions. These large molecules are often composed of smaller, distinct structural and functional units called protein domains. These domains can operate somewhat independently, acting like specialized tools within a larger machine. Among the many identified protein domains, the Tudor domain is a particularly versatile and widely distributed module found across diverse organisms. Its significance stems from its ability to recognize and interact with specific chemical modifications on other proteins, playing a part in fundamental cellular processes.
Defining the Tudor Domain
The Tudor domain is a conserved protein structural motif, typically about 60 amino acids long. It forms a characteristic five-stranded antiparallel beta-barrel structure, which is a common fold in proteins. A key feature within this structure is an “aromatic-binding cage” composed of several aromatic amino acid residues. This cage is essential for the domain’s function as a “reader” module.
Tudor domains recognize and bind specific post-translational modifications, especially methylated or acetylated lysine and arginine residues on other proteins. This interaction often occurs through cation-pi interactions between the modified amino acid and the aromatic residues within the Tudor domain’s binding cage. Depending on the specific Tudor domain, this binding can be highly selective for different methylation states, such as mono-, di-, or trimethylation. By acting as a recognition platform for these modifications, Tudor domains are involved in cellular signaling, translating these modifications into specific protein interactions and cellular responses.
Core Functions in the Cell
Tudor domains participate in a wide range of biological processes by recognizing methylated proteins. Binding these marks allows them to coordinate cellular responses in gene expression, RNA processing, and DNA repair. This recognition interprets the “histone code,” the pattern of modifications on histone proteins influencing gene activity.
In gene expression, Tudor domains are involved in chromatin modification. For example, the human TDRD3 protein, containing a Tudor domain, binds methylated arginine residues and promotes the transcription of estrogen-responsive elements. Other Tudor domain-containing proteins, like Polycomb-like (PCL) proteins, act as adaptors to recruit components that repress transcription by promoting histone methylation. The Tudor domain of PHF1 binds to trimethylated lysine 36 on histone H3, enhancing DNA unwrapping from nucleosomes and increasing accessibility for other factors.
Tudor domains also play roles in RNA processing and metabolism. Many Tudor domain proteins in RNA metabolism have extended structures and often contain additional RNA-binding motifs. They regulate aspects like RNA processing, stability, translation, and small RNA pathways. For example, the Survival Motor Neuron (SMN) protein, which contains a Tudor domain, is essential for assembling small nuclear ribonucleoproteins (snRNPs) for proper RNA splicing.
Tudor domains are involved in DNA repair pathways. The human p53-binding protein 1 (TP53BP1) is a Tudor domain-containing protein that responds to DNA damage. Its tandem Tudor domain recognizes and binds to dimethylated lysine 20 on histone H4 at sites of DNA double-strand breaks, helping to recruit other repair factors and orchestrate the DNA damage response. This illustrates how Tudor domains function as molecular adaptors, linking specific modifications to the assembly of protein complexes that carry out various cellular tasks.
Link to Disease and Therapeutics
Dysfunction or misregulation of proteins containing Tudor domains can contribute to the development and progression of various human diseases. Their involvement in fundamental cellular processes like gene expression, RNA metabolism, and DNA repair means their disruption can have significant health implications.
In cancer, several Tudor domain-containing proteins have been implicated in disease progression. For instance, Tudor domain-containing protein 3 (TDRD3) promotes the growth and invasive capacity of breast cancer cells. Overexpression of other Tudor domain proteins, such as Jumonji domain-containing (JMJD2) family proteins (e.g., KDM4C), is frequently observed in breast cancer and can function as oncogenes. The Tudor domain protein PHF20L1 is also linked to breast cancer, with its amplification and overexpression associated with shorter patient survival. These examples show how alterations in Tudor domain protein function can drive oncogenesis and tumor suppression.
Tudor domain protein dysfunction is also connected to neurodegenerative disorders. Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from reduced levels of functional SMN protein. Mutations within the SMN protein’s Tudor domain, such as E134K, severely impair its ability to interact with other proteins essential for RNA splicing, disrupting snRNP assembly and contributing to the disease. This demonstrates a link between defects in Tudor domain function and neurological conditions.
The involvement of Tudor domains in these diseases makes them potential targets for therapeutic development. Understanding how these domains recognize and bind their specific targets could lead to the design of small molecules that modulate their activity. Such interventions could correct dysfunction in diseases like cancer or neurodegenerative disorders, offering new treatment avenues.
Why It’s Called Tudor
The name “Tudor” for this protein domain has an interesting historical origin, stemming from its initial discovery in the fruit fly, Drosophila melanogaster. The domain was first identified in a protein called Tudor, which is essential for embryonic development and fertility in fruit flies.
The Drosophila Tudor gene plays a role in the formation of germ cells, which are the precursors to egg and sperm. Mutations in this gene lead to a distinct developmental defect in fly embryos. Mutant flies exhibit an abnormal phenotype where the posterior part of their abdomen fails to develop correctly. This characteristic “tud” or “tudor” appearance, due to the undeveloped posterior, gave the protein and its conserved module its name.