New Bioinformatic Insight into CD44: Classification of Human Variants and Structural Analysis of CD44 Targeting

The cluster of differentiation 44 (CD44) is a member of the hyaluronic acid (HA) receptor family of cell adhesion molecules. Besides HA, this transmembrane protein also serves as a receptor for other components of the extracellular matrix (ECM), including fibronectin, collagen, and osteopontin (OPN). The CD44-HA axis is involved in a wide range of physiological and cancer-related processes, particularly in cell adhesion and migration, lymphocyte activation, as well as tumour progression and metastasis. The possibility of modulating the CD44-HA interaction with a pharmacological inhibitor has therefore been recognized as an emerging anti-cancer strategy. With its expression in a wide variety, CD44 has also become the most common surface biomarker of cancer stem cells. Due to the rapid progress of research on this crucial receptor, some published and deposited variants were often poorly described or lacked accession numbers in the available protein databases, which created confusion and hindered relevant research. In this work, we attempted to examine the protein sequences of the known CD44 variants and match them between the two UniProt and the National Centre for Biotechnology Information (NCBI) Protein databases. The deposited sequences were aligned to the CD44 canonical sequence and grouped based on the observed differences. Analysis of CD44-ligand experimental structures available in the Protein Data Bank (PDB) was also performed to identify the most promising small-molecule inhibitors of the CD44-HA interaction.