The Cell Surface Receptor CD44: NMR‐Based Characterization of Putative Ligands

Baggio, Carlo; Barile, Elisa; Sorbo, Gianluigi Di; Kipps, Thomas J.; Pellecchia, Maurizio

doi:10.1002/cmdc.201600039

Cited by 12 publications

(10 citation statements)

References 54 publications

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“…Besides that of heparin, the binding of OPN to hyaluronic acid (HA), another ubiquitous extracellular matrix glycosaminoglycan, , was tested (Figure S8). HA is composed of N -acetylglucosamine and glucuronic acid and binds to the abundant extracellular receptor CD44 through a conserved HA binding domain (CD44 HABD ). , OPN was also described as a binding partner of CD44 (with and without HA) . Given the polyanionic nature of HA and heparin, a similar mode of binding to OPN can be anticipated.…”

Section: Resultsmentioning

confidence: 99%

Hyperphosphorylation of Human Osteopontin and Its Impact on Structural Dynamics and Molecular Recognition

et al. 2021

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Protein phosphorylation is an abundant post-translational modification (PTM) and an essential modulator of protein functionality in living cells. Intrinsically disordered proteins (IDPs) are particular targets of PTM protein kinases due to their involvement in fundamental protein interaction networks. Despite their dynamic nature, IDPs are far from having random-coil conformations but exhibit significant structural heterogeneity. Changes in the molecular environment, most prominently in the form of PTM via phosphorylation, can modulate these structural features. Therefore, how phosphorylation events can alter conformational ensembles of IDPs and their interactions with binding partners is of great interest. Here we study the effects of hyperphosphorylation on the IDP osteopontin (OPN), an extracellular target of the Fam20C kinase. We report a full characterization of the phosphorylation sites of OPN using a combined nuclear magnetic resonance/mass spectrometry approach and provide evidence for an increase in the local flexibility of highly phosphorylated regions and the ensuing overall structural elongation. Our study emphasizes the simultaneous importance of electrostatic and hydrophobic interactions in the formation of compact substates in IDPs and their relevance for molecular recognition events.

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Section: Resultsmentioning

confidence: 99%

Hyperphosphorylation of Human Osteopontin and Its Impact on Structural Dynamics and Molecular Recognition

et al. 2021

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“…uPA-A6-CD44 + -ENaC cascade regulates the fate of AT2 cells in re-alveolarization (24). uPA possesses a A6 motif showing high affinity with CD44 receptors (33,34). Elevated PAI-1 may interrupt the uPA-CD44 receptor binding competitively.…”

Section: Discussionmentioning

confidence: 99%

PAI-1 regulates AT2-mediated re-alveolarization and ion permeability

Ali

Zhang

Chang

et al. 2023

Preprint

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Background Acute lung injury is characterized by overwhelmingly elevated PAI-1 in both lung edema fluid and the circulating system. The role of increased PAI-1, encoded by Serpine1 gene, in the regeneration of injured lung epithelium has not been understood completely. This study aimed to investigate the role of Serpine1 in the regulation of alveolar type 2 epithelial cell (AT2) fate in a humanized mouse line carrying diseased mutants (Serpine1Tg). Methods Wild type (wt) and Serpine1Tg AT2 cells were either cultured as monolayers or 3D alveolospheres. Colony forming assay and total surface area of organoids were analyzed. AT1 and AT2 cells in organoids were counted by immunohistochemistry and fluorescence-activated cell sorting (FACS). To test the potential effects of elevated PAI-1 on the permeability in the epithelial monolayers, we digitized the biophysical properties of polarized AT2 monolayers grown at the air-liquid interface. Results A significant reduction in total AT2 cells harvested in Serpine1Tg mice was observed compared with wt controls. AT2 cells harvested from Serpine1Tg mice reduced significantly over the wt controls. Spheroids formed by Serpine1Tg AT2 cells were lesser than wt control. Similarly, the corresponding surface area, a readout of realveolarization of injured epithelium, was markedly reduced in Serpine1Tg organoids. FACS analysis revealed a significant suppression in the number of AT2 cells, in particular, the CD44+ subpopulation, in Serpine1Tg organoids. A lesser ratio of AT1:AT2 cells in Serpine1Tg organoids was observed compared with wt cultures. There was a significant increase in transepithelial resistance but not amiloride inhibition. Conclusions Our study suggests elevated PAI-1 in injured lungs downregulates alveolar epithelial regeneration by reducing the AT2 self-renewal, particularly in the CD44+ cells.

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“…Some studies have indicated that this peptide is a noncompetitive antagonist for the uPA‐uPAR complex, and some have shown that this peptide has homology with a part of CD44 (120‐NASAPPEE‐127) and introduced this protein as the A6 receptor 27,92 . In a structural biology study, 40 Baggio et al showed that the HA‐binding domain is probably part of CD44 that interacts with A6. But due to the use of a non‐glycosylated protein (this domain of CD44 has several glycosylated sites), they could not recognize the exact binding pocket of A6.…”

Section: Discussionmentioning

confidence: 99%

Rational peptide design for targeting cancer cell invasion

Gomari,

Arab,

Balalaie

et al. 2023

Proteins

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Cell invasion is an important process in cancer progression and recurrence. Invasion and implantation of cancer cells from their original place to other tissues, by disabling vital organs, challenges the treatment of cancer patients. Given the importance of the matter, many molecular treatments have been developed to inhibit cancer cell invasion. Because of their low production cost and ease of production, peptides are valuable therapeutic molecules for inhibiting cancer cell invasion. In recent years, advances in the field of computational biology have facilitated the design of anti‐cancer peptides. In our investigation, using computational biology approaches such as evolutionary analysis, residue scanning, protein–peptide interaction analysis, molecular dynamics, and free energy analysis, our team designed a peptide library with about 100 000 candidates based on A6 (acetyl‐KPSSPPEE‐amino) sequence which is an anti‐invasion peptide. During computational studies, two of the designed peptides that give the highest scores and showed the greatest sequence similarity to A6 were entered into the experimental analysis workflow for further analysis. In experimental analysis steps, the anti‐metastatic potency and other therapeutic effects of designed peptides were evaluated using MTT assay, RT‐qPCR, zymography analysis, and invasion assay. Our study disclosed that the IK1 (acetyl‐RPSFPPEE‐amino) peptide, like A6, has great potency to inhibit the invasion of cancer cells.

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The Cell Surface Receptor CD44: NMR‐Based Characterization of Putative Ligands

Cited by 12 publications

References 54 publications

Hyperphosphorylation of Human Osteopontin and Its Impact on Structural Dynamics and Molecular Recognition

Hyperphosphorylation of Human Osteopontin and Its Impact on Structural Dynamics and Molecular Recognition

PAI-1 regulates AT2-mediated re-alveolarization and ion permeability

Rational peptide design for targeting cancer cell invasion

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