Biology subjects

Rahimi, N.

Publications and source records attributed to Rahimi, N..

10 recordsLinked to original sources

bioRxiv2025

Flexible Motion of T7 bacteriophage Tail Fibers Suggest a Dynamic Viral Infection Mechanism

Viruses are nanoscale infectious agents capable of specifically targeting and reprograming host cells. A unique group of viruses, bacteriophages, have regained popularity in research partly due to the rising number of multidrug-resistant bacterial infections. Phages could potentially replace antibiotics, but only if we understand every detail of their structure and infection cycle. T7 bacteriophages are a group of dsDNA viruses, which infect E. coli bacteria. T7 virions are comprised of an icosahedral protein shell which encapsulates the genomic DNA, and a tail-fiber complex which is primarily used for target recognition and DNA injection. The virus has six" L"-shaped, [~]40 nm long fibers (gp17 protein trimers) attached to the tail-tube, which are thought to be essential for initial host recognition and possibly surface exploration. Using high-speed atomic force microscopy (HS-AFM) and molecular dynamics (MD) simulations combined with small angle X-ray scattering (SAXS) we observed the molecular structure and movements of isolated tail fibers. Firstly, we have identified a hinge region within the fibers, which makes them highly flexible, allowing the bending of their distal region. Furthermore, we have observed the dynamic triple helical coiled coil structure of the proximal region, which would allow fiber rotation. These two points of flexibility allow a more efficient and highly dynamic host recognition and virus anchoring process. The observed flexibility might allow host surface exploration by walking. Such flexibility in the host recognition machinery may not be unique to T7 bacteriophages, getting us one step closer to understanding the intricate details of virus-host interactions.

biophysics↗

bioRxiv2025

Effects of Visual Deprivation on Gait Stability During Treadmill Walking: Insights from a Bipedal Model

Walking, a fundamental daily activity, relies on sensory input from the somatosensory, visual, and vestibular systems, with vision playing a key role in providing information. When vision is impaired, individuals adjust their walking patterns to maintain stability. This study developed a simplified sagittal model to examine how visual deprivation affects treadmill walking at a controlled speed while ensuring dynamic stability. The model provides a framework for exploring outcomes that are challenging to assess experimentally. We hypothesized that the model would align with experimental data on step frequency, step length, and stability while predicting the steps that could lead to falls without vision. This study presents a bipedal model with two degrees of freedom, controlled by a hierarchical system. Two bio-inspired constraints were implemented: a speed constraint to match with treadmill pace, and a stability constraint to maintain walking stability. The weight of the feedback signal related to joint angles was modified to simulate vision loss. Visual deprivation increased step frequency and decreased step length to prevent falls. Additionally, prolonged deprivation led to step length fluctuations and increased constraint errors, ultimately causing falls. These findings align with human data, validating the potential of the model for rehabilitation research in individuals with visual impairments.

bioengineering↗

bioRxiv2024

Targeting GSK-beta with Peptide Inhibitors: A Rational Computational Strategy for Alzheimer's Disease Intervention

Glycogen synthase kinase-3 beta (GSK-3{beta}) is a pivotal serine/threonine kinase implicated in Alzheimers disease (AD) pathogenesis, particularly through the hyperphosphorylation of tau protein and increased production of amyloid-beta (A{beta}) peptides. This study investigates kappa casein-derived peptides as potential inhibitors of GSK-3{beta}. A peptide library of 42 sequences was generated from kappa casein and docking studies identified IP8 (LRFFVAPFPE) as the top candidate for binging to the previously approved inhibition site of GSK-3{beta}. Molecular dynamics (MD) simulations revealed that IP8s first three residues contributed unfavorably to binding, promoting the design of mutated peptides (MPs) MP27, MP31, and MP39. Of these, MP31 (HPDFVAPFPE) demonstrated the most stable interaction with GSK-3{beta}, exhibiting the most favorable binding score (-96.6) and interacting with 19 residues of the ATP-binding pocket of the enzyme. Structural analyses confirmed MP31s superior stability, with minimal RMSD deviations, and stable hydrogen bond formation. The results showed that peptide binding stabilizes GSK-3{beta} by reducing both domain-level dynamics and local side-chain flexibility, leading to a more structurally constrained enzyme. This dual stabilization of the backbone and side chains underscores the critical role of peptide interactions in modulating the conformational landscape of GSK-3{beta} and potentially obstructing substrate access or product release, which are crucial for enzyme activity. These results suggest that kappa casein-derived peptides, particularly MP31, could be promising therapeutic candidates for inhibiting GSK-3{beta} in AD.

biochemistry↗

bioRxiv2024

IGPR-1 is phosphorylated on the immunoreceptor tyrosine-based motif, stimulates AKT pathway and supports melanoma growth

Melanoma is a lethal form of skin cancer that impacts one out of every five Americans and ranks as the fifth most prevalent cancer among men and women in the United States. Immunoglobulin (Ig) and Proline-rich Receptor-1 (IGPR-1, also called TMIGD2/CD28H) is closely related to immune checkpoint, CD28/PDL1 family receptors. It controls important cellular processes including, immune cell regulation, cell-cell adhesion, mechanosensing, autophagy, and angiogenesis, and its activity is associated with multiple human malignancies. However, the role and signaling mechanism of IGPR-1 in melanoma remains largely undefined. Here, we report that IGPR-1 is mutated or upregulated in nearly 13% of melanoma and its pro-tumor signaling in melanoma cells is mediated by phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM) tyrosine (Y222). IGPR-1 is phosphorylated at Y222 in human melanoma and cell culture. Phosphorylation of Y222 is context-dependent and is catalyzed by EGFR and Src kinase. Inhibition of EGFR by pharmacological and shRNA strategies inhibited phosphorylation of Y222, whereas stimulation with EGF promoted phosphorylation of Y222 in vivo and recombinant active EGFR catalyzed its phosphorylation in an in vitro kinase assay. In vivo co-immunoprecipitation and in vitro GST-pull-down assays demonstrated that phospho-Y222 facilitates the binding of IGPR-1 with the SH2 domain-containing proteins, SHC1 and SHP2. IGPR-1 stimulates multiple key signal transduction pathways relevant to tumorigenesis, including AKT, mTOR, and MAPK. Mutation of Y222 blocked IGPR-1-mediated activation of AKT and MAPK leading to inhibition of 3D-spheroid tumor growth. By investigating the immunoreceptor tyrosine-based motif signaling of IGPR-1, this study uncovers new findings that could have significant diagnostic and therapeutic implications for melanoma.

cancer biology↗

bioRxiv2021

The Cell Adhesion Molecule TMIGD1 Binds to Moesin and Regulates Tubulin Acetylation and Cell Migration

BackgroundThe cell adhesion molecule transmembrane and immunoglobulin (Ig) domain containing1 (TMIGD1) is a novel tumor suppressor that plays important roles in regulating cell-cell adhesion, cell proliferation and cell cycle. However, the mechanisms of TMIGD1 signaling are not yet fully elucidated. ResultsTMIGD1 binds to the ERM family proteins moesin and ezrin, and an evolutionarily conserved RRKK motif on the carboxyl terminus of TMIGD1 mediates the interaction of TMIGD1 with the N-terminal ERM domains of moesin and ezrin. TMIGD1 governs the apical localization of moesin and ezrin, as the loss of TMIGD1 in mice altered apical localization of moesin and ezrin in epithelial cells. In cell culture, TMIGD1 inhibited moesin-induced filopodia-like protrusions and cell migration. More importantly, TMIGD1 stimulated the Lysine (K40) acetylation of -tubulin and promoted mitotic spindle organization and CRISPR/Cas9-mediated knockout of moesin impaired the TMIGD1-mediated acetylation of -tubulin and filamentous (F)-actin organization. ConclusionsTMIGD1 binds to moesin and ezrin, and regulates their cellular localization. Moesin plays critical roles in TMIGD1-dependent acetylation of -tubulin, mitotic spindle organization and cell migration. Our findings offer a molecular framework for understanding the complex functional interplay between TMIGD1 and the ERM family proteins in the regulation of cell adhesion and mitotic spindle assembly, and have wide-ranging implications in physiological and pathological processes such as cancer progression.

cell biology↗

bioRxiv2021

NEDD4 Regulates Ubiquitination and Stability of the Cell adhesion Molecule IGPR-1 via Lysosomal Pathway

The cell adhesion molecule immunoglobulin and proline-rich receptor-1 (IGPR-1) regulates various critical cellular processes including, cell-cell adhesion, mechanosensing and autophagy. However, the molecular mechanisms governing IGPR-1 cell surface expression levels remains unknown. In the present study, we used an in vitro ubiquitination assay and identified ubiquitin E3 ligase NEDD4 and the ubiquitin conjugating enzyme UbcH6 involved in the ubiquitination of IGPR-1. In vitro GST-pulldown and in vivo co-immunoprecipitation assays demonstrated that NEDD4 binds to IGPR-1. Over-expression of wild-type NEDD4 downregulated IGPR-1 and deletion of WW domains (1-4) of NEDD4 revoked its effects on IGPR-1. Similarly, knockdown of NEDD4 increased IGPR-1 levels in A375 melanoma cells. Furthermore, deletion of 57 amino acids encompassing polyproline rich (PPR) motif on the C-terminus of IGPR-1 nullified the binding of NEDD4 with IGPR-1. Moreover, we demonstrate that NEDD4 promotes K48- and K63-dependent polyubiquitination of IGPR-1. The NEDD4-mediated polyubiquitination of IGPR-1 stimulated lysosomal degradation of IGPR-1 as the treatment of cells with the lysosomal inhibitors, bafilomycine and ammonium chloride increased IGPR-1 levels in the HEK-293 cells ectopically expressing IGPR-1 and in multiple human skin melanoma cell lines. Hence, these findings suggest that ubiquitin E3 ligase NEDD4 is a key regulator of IGPR-1 with a significant implication in the therapeutic targeting of IGPR-1.

cell biology↗

bioRxiv2020

CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells

As the COVID-19 pandemic continues to spread, investigating the processes underlying the interactions between SARS-CoV-2 and its hosts is of high importance. Here, we report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells. Immunofluorescence staining of human tissues revealed prominent expression of CD209L in the lung and kidney epithelium and endothelium. Multiple biochemical assays using a purified recombinant SARS-CoV-2 spike receptor binding domain (S-RBD) or S1 encompassing both NTB and RBD and ectopically expressed CD209L and CD209 revealed that CD209L and CD209 interact with S-RBD. CD209L contains two N-glycosylation sequons, at sites N92 and N361, but we determined that only site N92 is occupied. Removal of the N-glycosylation at this site enhances the binding of S-RBD with CD209L. CD209L also interacts with ACE2, suggesting a role for heterodimerization of CD209L and ACE2 in SARS-CoV-2 entry and infection in cell types where both are present. Furthermore, we demonstrate that human endothelial cells are permissive to SARS-CoV-2 infection and interference with CD209L activity by knockdown strategy or with soluble CD209L inhibits virus entry. Our observations demonstrate that CD209L and CD209 serve as alternative receptors for SARS-CoV-2 in disease-relevant cell types, including the vascular system. This property is particularly important in tissues where ACE2 has low expression or is absent, and may have implications for antiviral drug development.

cell biology↗

bioRxiv2020

TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

Colorectal cancer (CRC) is a leading non-familial cause of cancer mortality among men and women. Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remains incompletely understood. In this study, we demonstrate that cell adhesion molecule transmembrane and immunoglobulin domain containing1 (TMIGD1) is highly expressed in mouse and human normal intestinal epithelial cells. We have developed TMIGD1 knockout mice and show that the loss of TMIGD1 in mice results in the development of adenomas in small intestine and colon. Additionally, the loss of TMIGD1 in mouse impaired intestinal epithelium brush border formation, junctional polarity and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation, cell migration, arrests cell cycle at G2/M phase and induces expression of p21CIP1 (cyclin-dependent kinase inhibitor 1), and p27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, we demonstrate that TMIGD1 is progressively downregulated in sporadic human CRC and correlates with poor overall survival. Our findings identify TMIGD1 as a novel tumor suppressor gene and provide insights into the pathogenesis of colorectal cancer and possibilities as a potential therapeutic target.

cancer biology↗

bioRxiv2020

Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy

Immunoglobulin (Ig) and proline-rich receptor-1 (IGPR-1) is a cell adhesion molecule that regulates angiogenesis and endothelial barrier function. IGPR-1 is activated by shear stress and mediates endothelial cells response to shear stress. Autophagy plays critical roles in the maintenance of endothelial cells in response to cellular stress caused by blood flow. However, whether IGPR-1 is activated in response to, and mediates autophagy remains unknown. In this study, we demonstrate that IGPR-1 is activated by autophagy inducing stimuli, such as amino acid starvation, nutrient deprivation, rapamycin and lipopolysaccharide (LPS). We have identified I{kappa}B kinase{beta} (IKK{beta}) as a key serine/threonine kinase activated by autophagy stimuli and mediates phosphorylation of IGPR-1 at Ser220. Activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase (AMPK), which leads to phosphorylation of key pro-autophagy proteins, ULK1 and Beclin-1 (BECN1), increased LC3-II levels and accumulation of LC3 punctum. This study demonstrates that IGPR-1 is activated by and regulates autophagy, connecting cell adhesion to autophagy, a finding that has important significance for autophagy-driven pathologies such cardiovascular diseases and cancer.

cell biology↗

bioRxiv2018

Dynamics of Spaetzle morphogen shuttling in the Drosophila embryo shapes pattern

Establishment of morphogen gradients in the early Drosophila embryo is challenged by a diffusible extracellular milieu, and rapid nuclear divisions that occur at the same time. To understand how a sharp gradient is formed within this dynamic environment, we followed the generation of graded nuclear Dorsal (Dl) protein, the hallmark of pattern formation along the dorso-ventral axis, in live embryos. We show that a sharp gradient is formed through extracellular, diffusion-based morphogen shuttling that progresses through several nuclear divisions. Perturbed shuttling in wntD mutant embryos results in a flat activation peak and aberrant gastrulation. Re-entry of Dl into the nuclei at each cycle refines the signaling output, by guiding graded accumulation of the T48 transcript that drives patterned gastrulation. We conclude that diffusion-based ligand shuttling, coupled with dynamic readout, establishes a refined pattern within the diffusible environment of early embryos.

bioinformatics↗