Proteins are complex molecules within all living organisms, performing a vast array of tasks necessary for life. These large molecules are often composed of smaller, distinct structural and functional units known as protein domains. Each domain typically folds independently and contributes a specific function to the overall protein. The WW domain represents one such small, yet important, protein domain, involved in various biological processes.
What Exactly is a WW Domain?
The WW domain is a compact protein module, consisting of 35 to 40 amino acid residues. Its name, “WW,” originates from two conserved tryptophan amino acids (tryptophan’s single-letter code is W) within its sequence, spaced 20-22 amino acids apart. These two tryptophan residues are important for its characteristic triple-stranded beta sheet structure. This small structural motif allows the WW domain to mediate specific interactions between proteins.
Where WW Domains Are Found and What They Interact With
WW domains are found across diverse organisms, from yeast to humans, and in many unrelated proteins. The human proteome contains at least 51 WW domain-containing proteins. Many proteins contain multiple WW domains, sometimes up to four, allowing interaction with multiple targets or different parts of the same target.
These domains primarily bind to short peptide sequences rich in proline, particularly the PPxY (or PY) motif (P=proline, x=any amino acid, Y=tyrosine). Some WW domains also bind to motifs containing phosphoserine or phosphothreonine residues. This binding recruits other proteins, forming complexes involved in various cellular activities.
Key Functions of WW Domains in the Body
WW domains participate in many cellular processes by forming multiprotein networks. They are involved in the ubiquitin-proteasome system (UPS), often interacting with E3 ubiquitin ligases like the NEDD4 family. These interactions mark proteins for degradation, maintaining cellular balance and removing damaged or excessive proteins.
WW domains also function in cell signaling pathways, bringing signaling molecules together to transmit information. For instance, they are involved in the Hippo signaling pathway, which regulates cell growth and proliferation. Their interactions assemble regulatory protein complexes that influence cell behavior.
Beyond degradation and signaling, WW domains regulate gene expression by interacting with transcription factors. They are also involved in RNA processing, including pre-mRNA splicing and polyadenylation, by binding to components of these molecular machines. These varied roles impact cell health and function.
WW Domains and Their Link to Disease
Dysregulation or mutations in WW domain-containing proteins can lead to various human diseases. In cancer, WW domains regulate cell growth, division, and tumor suppression. Proteins like YAP and TAZ, which contain WW domains, are part of the Hippo pathway and are implicated in tumorigenesis, making them potential therapeutic targets.
WW domain dysfunction is also linked to neurological disorders. The tumor suppressor WWOX gene, containing WW domains, is a risk factor in Alzheimer’s disease. Certain neurodegenerative diseases, such as Huntington’s disease, are also associated with WW domain-mediated interactions.
WW domain proteins also contribute to metabolic disorders. Liddle’s syndrome, a genetic disorder with severe hypertension, results from mutations affecting ion channel regulation, where WW domain proteins interact with these channels. While cystic fibrosis is caused by CFTR protein mutations, some WW domain proteins interact with CFTR, highlighting their relevance in cellular function and disease. Understanding these connections provides avenues for new therapeutic approaches.