Structural insights into the modulation of PDGF/PDGFR-β complexation by hyaluronan derivatives

Abstract

Angiogenesis is an important physiological process playing a crucial role in wound healing and cancer progression. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are key players in angiogenesis. Based on previous findings regarding the modulation of VEGF activity by glycosaminoglycans (GAG), here we explore the interaction of hyaluronan (HA)-based GAG with PDGF and its receptor PDGFR-β by applying molecular modeling and dynamics simulations in combination with surface plasmon resonance (SPR). Computational analysis on the interaction of oligo-hyaluronan derivatives with different sulfation pattern and functionalization shows that these GAG interact with PDGF in relevant regions for receptor recognition, and that high sulfation as well as modification with the TAMRA group convey stronger binding. On the other hand, the studied oligo-hyaluronan derivatives are predicted to scarcely recognize PDGFR-β. SPR results are in line with the computational predictions regarding the binding pattern of HA tetrasaccharide (HA4) derivatives to PDGF and PDGFR-β. Furthermore, our experimental results also show that the complexation of PDGF to PDGFR-β can be modulated by HA4 derivatives. The results found open the path for considering HA4 derivatives as potential candidates to be exploited for modulation of the PDGF/PDGFR-β signaling system in angiogenesis and related disease conditions.

A Positive Feedback Loop between Inactive VHL-Triggered Histone Lactylation and PDGFRβ Signaling Drives Clear Cell Renal Cell Carcinoma Progression

“…An increase in the expression of PDGFRβ was seen in multiple tumors, including gastrointestinal tumor, lung cancer, breast cancer, hepatocellular carcinoma, and pancreatic cancer 31 . Moreover, PDGFRβ signaling was identified to facilitate cell proliferation, metastasis, and angiogenesis of tumors by activating PI3K/AKT and Ras/MAPK pathways 32 . Our results found PDGFβ stimulation in ccRCC cells led to an increase in glycolysis, lactate production, as well as histone lactylation, which in turn activated PDGFRβ transcription, thereby forming a vicious cycle that further accelerates the progression of ccRCC.…”

Vaginal reconstruction with a double-sided biomembrane—a preclinical experimental study on large animals

“…Proteomic analysis also revealed that the DBM contains many components that regulate cell behavior and function. For example, fibronectin and laminin (LAMC1 and LAMB2) are used to increase cell adhesion, 26 PDGFR-β plays an important role in the process of early hematopoiesis and blood vessel formation, 41 and PGs facilitate the binding of growth factors, ensuring good cell adhesion, migration, growth, and proliferation. 25,42 Biomaterials possess mechanical properties similar to original tissues, which not only provide a biomimetic mechanical environment to mediate biological behavior and function during tissue regeneration, but are also helpful for preventing contraction, expansion, or stretching during reconstruction.…”

Atomic-Resolution Experimental Structural Biology and Molecular Dynamics Simulations of Hyaluronan and Its Complexes

“…Sulfated hyaluronan was shown to have a clear binding pose in its complex with the TGF-β1/TβR-I/TβR-II complex that is energetically favorable and electrostatically driven, in contrast to non-sulfated hyaluronan, and a particular lysine residue in TβR-I is key to interactions with sulfated hyaluronan carboxylate and sulfate functional groups [ 158 ]. Similarly, non-sulfated hyaluronan oligosaccharide barely interacts with the complex of PDGF and its receptor PDGFR-β, whereas chemical sulfation of hyaluronan substantially increases its binding [ 159 ]. While directly getting estimates of binding free energies from standard atomic-resolution explicit-solvent molecular dynamics simulation is a difficult task, it is relatively easy to do so by applying a continuum solvent approximation to snapshots taken from explicit-solvent molecular dynamics trajectories using the molecular mechanics Poisson-Boltzman surface area (MM-PBSA) or molecular mechanics generalized Born surface area (MM-GBSA) methods [ 160 , 161 , 162 , 163 ], and these methods are useful tools in the context of glycosaminoglycan–protein binding [ 164 ], including as applied to the hyaluronan–cytokine complexes above.…”