The protein WDR77, also known as Methylosome Protein 50 (MEP50), belongs to a large family of proteins characterized by a WD repeat structure. This feature enables WDR77 to interact with other molecules, forming the basis for its diverse roles in fundamental cellular processes.
WDR77’s Role in Protein Modification and RNA Processing
A primary function of WDR77 is its role as a component of a cellular machine called the methylosome. WDR77 is a non-catalytic part of this complex, meaning it helps the machine function without performing the chemical reaction itself. The methylosome’s job is to carry out protein methylation, where it attaches small chemical tags called methyl groups to other proteins. This modification can alter a protein’s function, stability, or location within the cell.
Within the methylosome, WDR77 works alongside the enzyme PRMT5. WDR77 acts as an adaptor, recruiting specific proteins to the PRMT5 enzyme for accurate modification.
One of the most well-understood roles of the WDR77/PRMT5 complex is the modification of a group of proteins called spliceosomal Sm proteins. These Sm proteins are components of the spliceosome, the cellular machinery responsible for processing ribonucleic acid (RNA). After a gene is transcribed into a precursor RNA molecule, the spliceosome edits it by cutting out unnecessary sections to produce a mature messenger RNA (mRNA). The methylation of Sm proteins by the methylosome is a necessary step for their assembly into these spliceosome particles.
WDR77 in Gene Expression and Cellular Signaling
WDR77 is directly involved in controlling which genes are turned on or off by functioning as a cofactor for the androgen receptor (AR). The AR becomes active in response to male hormones like testosterone, and WDR77 helps it regulate target genes. This interaction supports normal male development and reproductive health.
This partnership illustrates WDR77’s function in signal transduction, the process by which cells respond to their environment. When a hormone like testosterone binds to the androgen receptor, it initiates a signaling cascade that changes gene expression. WDR77 enhances the receptor’s transcriptional activity, boosting protein production from the genes it controls.
WDR77’s influence on gene expression is not limited to its work with the androgen receptor. It also acts as a cofactor for other steroid hormone receptors, including the estrogen receptor, modulating the expression of hormone-responsive genes. It also participates in other signaling networks that manage cell growth and gene regulation by interacting with proteins to either activate or repress gene activity depending on cellular needs.
The Significance of WDR77’s Cellular Location
WDR77’s function depends on its location within the cell, differing between the nucleus and the cytoplasm. This differential localization allows the protein to interact with distinct sets of partner proteins and participate in different cellular pathways.
In the nucleus, WDR77 is associated with gene regulation. It acts as a coactivator for transcription factors like the androgen and estrogen receptors, directly influencing which genes are expressed. The presence of WDR77 in the nucleus is linked to transcriptional activation and can affect cell proliferation depending on the cell type.
When WDR77 is in the cytoplasm, its functions change. A shift in location from the nucleus to the cytoplasm is noted in certain diseases, including some cancers. The movement of WDR77 between these compartments is a mechanism for modulating its activity and impact on cell behavior.
WDR77’s Implications for Cancer and Development
WDR77’s roles in gene expression and cell growth involve it in both normal development and diseases like cancer. Its functions are tied to processes such as the cell cycle, which governs how cells divide, and apoptosis, or programmed cell death.
WDR77 is expressed in various tissues, with high levels found in the testis, where it is also known as testis tissue sperm-binding protein Li 44a. This specific expression points to a role in sperm function or development. While its presence in other tissues indicates broader functions, its connection to the androgen receptor strengthens its link to male reproductive biology.
The protein’s link to cancer is complex. In prostate cancer, its role as an androgen receptor coactivator can promote cancer cell growth. The change in WDR77’s location from the nucleus to the cytoplasm is thought to be involved in the early stages of the disease. Germ-line mutations in the WDR77 gene have also been found to predispose individuals to familial papillary thyroid cancer.
The WDR77/PRMT5 interaction is also significant in cancer biology, as the complex can modify proteins involved in cell growth and survival, affecting tumor progression. For example, the WDR77/PRMT5 complex has been implicated in promoting cancer cell proliferation in breast cancer and other malignancies. Because of its influence on cancer cell growth, WDR77 is being investigated as a potential therapeutic target.