Biology subjects

Hashemi, H.

Publications and source records attributed to Hashemi, H..

3 recordsLinked to original sources

bioRxiv2021

Nanobody Mediated Macromolecular Crowding Induces Membrane Fission and Remodeling in the African Trypanosome

The dense Variant Surface Glycoprotein (VSG) coat of African trypanosomes represents the primary host-pathogen interface. Antigenic variation prevents clearing of the pathogen by employing a large repertoire of antigenically distinct VSG genes, thus neutralizing the hosts antibody response. To explore the epitope space of VSGs, we generated anti-VSG nanobodies and combined high-resolution structural analysis of VSG-nanobody complexes with binding assays on living cells, revealing that these camelid antibodies bind deeply inside the coat. One nanobody caused rapid loss of cellular motility, possibly due to blockage of VSG mobility on the coat, whose rapid endo-and exocytosis is mechanistically linked to T. brucei propulsion and whose density is required for survival. Electron microscopy studies demonstrated that this loss of motility was accompanied by rapid formation and shedding of nanovesicles and nanotubes, suggesting that increased protein crowding on the dense membrane can be a driving force for membrane fission in living cells.

microbiology↗

bioRxiv2020

Integrated analysis of high throughput transcriptomic data revealed specific gene expression signature of cardiomyocytes

Acquiring a specific transcriptomic signature of the human and mouse cardiomyocyte (CM) will greatly increase our understanding of their biology and associated diseases that remain the most deadly across the world. In this study, using comprehensive transcriptomic mining of 91 cell types over 877 samples from bulk RNA-sequencing, single cell RNA-sequencing, and microarray techniques, we describe a unique 118-gene signature of human and mouse primary CMs. Once we had access to this CM-specific gene signature, we investigated the spatial heterogeneity of CMs throughout the heart tissue. Moreover, we compared the CM-specific gene signature to that of CMs derived from 10 differentiation protocols, and we identified the protocols that generate cells most similar to primary CMs. Finally, we looked at the specific differences between primary and differentiated CMs and found that differentiated cells underexpress genes related to CM development and maturity. The differentiated cells conversely overexpressed cell cycle-related genes, resulting in the progenitor features that remain in differentiated CMs compared to primary adult CMs. The presence of histone post translational modification H3K27ac from ChIP sequencing data sets were used to confirm transcriptomic findings. To the best of our knowledge, this is the most comprehensive study to date that unravels the unique transcriptomic signature of primary and differentiated CMs. This study provides important insights into our understanding of CM biology and the molecular mechanisms that make them such a unique cell type. Moreover, the specific transcriptomic signature of CMs could be used in developmental studies, stem cell therapy, regenerative medicine, and drug screening assays.

cell biology↗

bioRxiv2020

A Parasite Coat Protein Binds Suramin to Confer Drug Resistance

Suramin has been a primary early-stage treatment for African trypanosomiasis for nearly one hundred years. Recent studies revealed that trypanosome strains that express the Variant Surface Glycoprotein VSGsur possess heightened resistance to suramin. We show here that VSGsur binds tightly to suramin, other VSGs do not, and that together with VSG13 it defines a structurally divergent subgroup of these coat proteins. The co-crystal structure of VSGsur with suramin reveals that the chemically symmetric drug binds within a large cavity in the VSG homodimer asymmetrically, primarily through contacts of its central benzene rings. Structure-based, loss-of-contact mutations in VSGsur significantly decrease the affinity to suramin and lead to a loss of the resistance phenotype. Altogether, these data show that the resistance phenotype is dependent on the binding of suramin to VSGsur, establishing that the VSG proteins can possess functionality beyond their role in antigenic variation.

microbiology↗