Biology subjects

Rahmaninejad, H.

Publications and source records attributed to Rahmaninejad, H..

3 recordsLinked to original sources

bioRxiv2021

Crowding within synaptic junctions influence the degradation of adenoside nucleotides by CD39 and CD73 ectonucleotidases

1Synapsed cells can communicate using exocytosed nucleotides like adenosine triphosphate (ATP). Ectonucleotidases localized to a synaptic junction degrade such nucleotides into metabolites like adenosine monophosphate (AMP) or adenosine, oftentimes in a sequential manner. CD39 and CD73 are a representative set of coupled ectonucleotidases, where CD39 first converts ATP and adenosine diphosphate (ADP) into AMP, after which the AMP product is dephosphorylated into adenosine by CD73. Hence, CD39/CD73 help shape cellular responses to extracellular ATP. In a previous study [1] we demonstrated that the rates of coupled CD39/CD73 activity within synapse-like junctions are strongly controlled by the enzymes co-localization, their surface charge densities, and the electrostatic potential of the surrounding cell membranes. In this study, we demonstrate that crowders within a synaptic junction, which can include globular proteins like cytokines and membrane-bound proteins, impact coupled CD39/CD73 electronucleotidase activity and in turn, the availability of intrasynapse ATP. Specifically, we simulated a spatially-explicit, reaction-diffusion model for the coupled conversion of ATP[->]AMP and AMP[->]adenosine in a model synaptic junction with crowders via the finite element method. Our modeling results suggest that the association rate for ATP to CD39 is strongly influenced by the density of intrasynaptic protein crowders, as increasing crowder density suppressed ATP association kinetics. Much of this suppression can be rationalized based on a loss of configurational entropy. The surface charges of crowders can further influence the association rate, with the surprising result that favorable crowder/nucleotide electrostatic interactions can yield CD39 association rates that are faster than crowder-free configurations. However, attractive crowder/nucleotide interactions decrease the rate and efficiency of adenosine production, which in turn increases the availability of ATP and AMP within the synapse relative to crowder-free configurations. These findings highlight how CD39/CD73 ectonucleotidase activity, electrostatics and crowding within synapses influence the availability of nucleotides for intercellular communication.

cell biology↗

bioRxiv2021

Effect of membrane cholesterol on dynamical properties of solvent molecules

Membrane lipid composition is a critical feature of cell function, where cholesterol is a major lipid sterol component that influences the membranes physical and electrical properties. The effects of cholesterol on transport properties between adjacent to the cells, especially in junctions formed between cells is not completely understood. These junctions where substances transport and signaling is critical may be affected by modifying the cholesterol composition of the membrane in these junctional regions. Here we show how the cholesterol content in a membrane can regulate these phenomena by changing their effect on transport into and through regions between cell membranes in close proximity. Through geometric and electrostatic effects interaction with substrates, the properties of the fluid between membranes are shown to potentially enforce concentration gradients of dissolved compounds that may be biologically significant.

biophysics↗

bioRxiv2019

Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide pools

1Nucleotides comprise small molecules that perform critical signaling and energetic roles in biological systems. Of these, the concentrations of adenosine and its derivatives, including adenosine tri-, di-, and mono-phosphate are dynamically controlled in the extracellular-space by diphosphohydrolases and ecto-nucleotidases that rapidly degrade such nucleotides. In many instances, the close coupling between cells such as those in synaptic junctions yields tiny extracellular nanodomains, within which the charged nucleotides interact with densely-packed membranes and biomolecules. While the contributions of electrostatic and steric interactions within such nanodomains are known to shape diffusion-limited reaction rates, less is understood about how these factors control the kinetics of sequentially-coupled diphosphohydrolase/nucleotidase-catalyzed reactions. To rank the relative importance of these factors, we utilize reaction-diffusion numerical simulations to systematically probe coupled enzyme activity in narrow junctions. We perform these simulations in nanoscale geometries representative of narrow extracellular compartments, within which we localize sequentially- and spatially-coupled enzymes. These enzymes catalyze the conversion of a representative charged substrate such as adenosine triphosphate (ATP) into substrates with different net charges, such as adenosine monophosphate (AMP) and adenosine (Ado). Our modeling approach considers electrostatic interactions of diffusing, charged substrates with extracellular membranes, and coupled enzymes. With this model, we find that 1) Reaction rates exhibited confinement effects, namely reduced reaction rates relative to bulk, that were most pronounced when the enzyme was close to the pore size and 2) The presence of charge on the pore boundary further tunes reaction rates by controlling the pooling of substrate near the reactive protein akin to ions near trans-membrane proteins. These findings suggest how remarkable reaction efficiencies of coupled enzymatic processes can be supported in charged and spatially-confined volumes of extracellular spaces.

biophysics↗