Structural characterization of the CD44 stem region for standard and cancer-associated isoforms
Journal
International Journal of Molecular Sciences
Journal Volume
21
Journal Issue
1
Date Issued
2020
Author(s)
Abstract
CD44 is widely expressed in most vertebrate cells, whereas the expression of CD44v6 is restricted to only a few tissues and has been considered to be associated with tumor progression and metastasis. Thus, CD44v6 has been recognized as a promising prognostic biomarker and therapeutic target for various cancers for more than a decade. However, despite many experimental studies, the structural dynamics and differences between CD44s and CD44v6, particularly in their stem region, still remain elusive. Here, a computational study was conducted to address these problems. We found that the stem of CD44s adopted predominantly two conformations, one featuring antiparallel β-sheets and the other featuring parallel β-sheets, whereas the stem of CD44v6 adopted mainly one conformation with relatively highly suppressed β-sheet contents. Moreover, Phe215 was found to be essential in the β-sheets of both CD44s and CD44v6. We finally found intramolecular Phe215–Trp224 hydrogen-bonding interactions and hydrophobic interactions with Phe215 that cooperatively drove conformational differences upon the addition of the v6 region to CD44. Our study elucidated the structural differences between the stem regions of CD44s and CD44v6 and thus can offer useful structural information for drug design to specifically target CD44v6 in promising clinical applications. ? 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Subjects
CD44; CD44v6; Metastasis; Molecular dynamics simulations; Receptor tyrosine kinase (RTK); Tumor progression; β-sheets
SDGs
Other Subjects
CD44s antigen; CD44v6 antigen; Hermes antigen; phenylalanine; protein tyrosine kinase; tryptophan; unclassified drug; CD44 protein, human; hyaluronic acid binding protein; isoprotein; antigen structure; Article; beta sheet; cancer growth; hydrogen bond; hydrophobicity; malignant neoplasm; mathematical computing; metastasis; molecular dynamics; protein conformation; protein content; protein interaction; structure analysis; amino acid sequence; animal; chemical phenomena; chemistry; human; neoplasm; rat; Amino Acid Sequence; Animals; Humans; Hyaluronan Receptors; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Neoplasms; Protein Conformation; Protein Conformation, beta-Strand; Protein Isoforms; Rats
Type
journal article