Biology subjects

Khan, U.

Publications and source records attributed to Khan, U..

24 records · Page 2Linked to original sources

bioRxiv2021

Characterization and Structural Prediction of ORF10, ORF7b, ORF7a, ORF6, Membrane Glycoprotein, and Envelope Protein in SARS-CoV-2 Bangladeshi Variant through Bioinformatics Approach

The acute respiratory disease induced by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has become a global epidemic in just less than a year by the first half of 2020. The subsequent efficient human-to-human transmission of this virus eventually affected millions of people worldwide. The most devastating thing is that the infection rate is continuously uprising and resulting in significant mortality especially among the older age population and those with health co-morbidities. This enveloped, positive-sense RNA virus is chiefly responsible for the infection of the upper respiratory system. The virulence of the SARS-CoV-2 is mostly regulated by its proteins like entry to the host cell through fusion mechanism, fusion of infected cells with neighboring uninfected cells to spread the virus, inhibition of host gene expression, cellular differentiation, apoptosis, mitochondrial biogenesis, etc. But very little is known about the protein structures and functionalities. Therefore, the main purpose of this study is to learn more about these proteins through bioinformatics approaches. In this study, ORF10, ORF7b, ORF7a, ORF6, membrane glycoprotein, and envelope protein have been selected from a Bangladeshi Corona-virus strain G039392 and a number of bioinformatics tools (MEGA-X-V10.1.7, PONDR(R), ProtScale, ProtParam, SCRIBER, NetSurfP v2.0, IntFOLD, UCSF Chimera, and PyMol) and strategies were implemented for multiple sequence alignment and phylogeny analysis with 9 different variants, predicting hydropathicity, amino acid compositions, protein-binding propensity, protein disorders, 2D and 3D protein modeling. Selected proteins were characterized as highly flexible, structurally and electrostatically extremely stable, ordered, biologically active, hydrophobic, and closely related to the proteins of different variants. This detailed information regarding the characterization and structure of proteins of SARS-CoV-2 Bangladeshi variant was performed for the first time ever to unveil the deep mechanism behind the virulence features and also, this robust appraisal paves the future way for molecular docking, vaccine development targeting these characterized proteins.

bioinformatics↗

bioRxiv2021

Molecular mechanisms underlying enhanced hemichannel function of a cataract-associated Cx50 mutant

Connexin-50 (Cx50) is among the most frequently mutated genes associated with congenital cataracts. While most of these disease-linked variants cause loss-of-function due to misfolding or aberrant trafficking, others directly alter channel properties. The mechanistic bases for such functional defects are mostly unknown. We investigated the functional and structural properties of a cataract-linked mutant, Cx50T39R (T39R), in the Xenopus oocyte system. T39R exhibited greatly enhanced hemichannel currents with altered voltage-gating properties compared to Cx50 and induced cell death. Co-expression of mutant T39R with wild-type Cx50 (to mimic the heterozygous state) resulted in hemichannel currents whose properties were indistinguishable from those induced by T39R alone, suggesting that the mutant had a dominant effect. Co-expression with Cx46 also produced channels with altered voltage-gating properties, particularly at negative potentials. All-atom molecular dynamics simulations indicate that the R39 substitution can form multiple electrostatic salt-bridge interactions between neighboring subunits that could stabilize the open-state conformation of the N-terminal domain, while also neutralizing the voltage-sensing residue D3 as well as residue E42 which participates in loop-gating. Together, these results suggest T39R acts as a dominant gain-of-function mutation that produces leaky hemichannels that may cause cytotoxicity in the lens and lead to development of cataracts. Statement of significanceWe investigated the functional and structural properties of a cataract-linked mutant, Cx50T39R (T39R), in the Xenopus oocyte system and showed that T39R exhibited greatly enhanced hemichannel currents with altered voltage-gating properties compared to Cx50 and induced cell death. Consistent with our experimental findings, all-atom equilibrium state molecular dynamics (MD) simulations of T39R show that R39 stabilized the open-state configuration of the N-terminal (NT) domain from an adjacent subunit. These results suggest that T39R causes disease by preventing the hemichannels from closing when present in the plasma membrane in the undocked state and provide an atomistic rationalization for the Cx50 disease-linked phenotype. They also expand our understanding of how connexin hemichannel channel gating is controlled.

physiology↗

bioRxiv2020

Agro-morphological, yield, and genotyping-by-sequencing data of selected wheat germplasm

Wheat (Triticum aestivum) is the most important staple food in Pakistan. Knowledge of its genetic diversity is critical for designing effective crop breeding programs. Here we report agro-morphological and yield data for 112 genotypes (including 7 duplicates) of wheat (Triticum aestivum) cultivars, advance lines, landraces and wild relatives, collected from several research institutes and breeders across Pakistan. We also report genotyping-by-sequencing (GBS) data for a selected sub-set of 52 genotypes. Sequencing was performed using Illumina HiSeq 2500 platform using the PE150 run. Data generated per sample ranged from 1.01 to 2.5 Gb; 90% of the short reads exhibited quality scores above 99.9%. TGACv1 wheat genome was used as a reference to map short reads from individual genotypes and to filter single nucleotide polymorphic loci (SNPs). On average, 364,074{+/-}54479 SNPs per genotype were recorded. The sequencing data has been submitted to the SRA database of NCBI (accession number SRP179096). The agro-morphological and yield data, along with the sequence data and SNPs will be invaluable resources for wheat breeding programs in future.

genetics↗

bioRxiv2020

Connexin 46 and connexin 50 gap junction channel open stability and unitary conductance are shaped by structural and dynamic features of their N-terminal domains

The connexins form intercellular communication channels, known as gap junctions (GJs), that facilitate diverse physiological roles in vertebrate species, ranging from electrical coupling and long-range chemical signaling, to coordinating development and nutrient exchange. GJs formed by different connexins are expressed throughout the body and harbor unique channel properties that have not been fully defined mechanistically. Recent structural studies have implicated the amino-terminal (NT) domain as contributing to isoform-specific functional differences that exist between the lens connexins, Cx50 and Cx46. To better understand the structural and functional differences in the two closely related, yet functionally distinct GJs, we constructed models corresponding to CryoEM-based structures of the wildtype Cx50 and Cx46 GJs, NT domain swapped chimeras (Cx46-50NT and Cx50-46NT), and point variants at the 9th residue (Cx46-R9N and Cx50-N9R) for comparative MD simulation and electrophysiology studies. All of these constructs formed functional GJ channels, except Cx46-50NT, which correlated with increased dynamical behavior (instability) of the NT domain observed by MD simulation. Single channel conductance (γj) also correlated well with free-energy landscapes predicted by MD, where γj of Cx46-R9N was increased from Cx46 and the γjs of Cx50-46NT and Cx50-N9R was decreased from Cx50, but to a surprisingly greater degree. Additionally, we observed significant effects on transjunctional voltage-dependent gating (Vj-gating) and open-state dwell times induced by the designed NT domain variants. Together, these studies indicate that the NT domains of Cx46 and Cx50 play an important role in defining channel properties related to open-state stability and single channel conductance.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsGJgap junctionGjgap junctional coupling conductanceγjsingle gap junction channel conductanceIjmacroscopic transjunctional currentijsingle gap junction channel currentCx46sheep connexin 46Cx50sheep connexin 50Vjtransjunctional voltageMDmolecular dynamicsr.m.s.d.root mean square deviationr.m.s.f.root mean square fluctuationPMFpotential of mean forceView Full Text

biophysics↗

bioRxiv2018

Behavioral changes and growth deficits in a CRISPR engineered mouse model of the schizophrenia-associated 3q29 deletion

The 3q29 deletion confers increased risk for neuropsychiatric phenotypes including intellectual disability, autism spectrum disorder, generalized anxiety disorder, and a >40-fold increased risk for schizophrenia. To investigate consequences of the 3q29 deletion in an experimental system, we used CRISPR/Cas9 technology to introduce a heterozygous deletion into the syntenic interval on C57BL/6 mouse chromosome 16. mRNA abundance for 20 of the 21 genes in the interval was reduced by ~50%, while protein levels were reduced for only a subset of these, suggesting a compensatory mechanism. Mice harboring the deletion manifested behavioral impairments in multiple domains including social interaction, cognitive function, acoustic startle, and amphetamine sensitivity, with some sex-dependent manifestations. Additionally, 3q29 deletion mice showed reduced body weight throughout development consistent with the phenotype of 3q29 deletion syndrome patients. Of the genes within the interval, DLG1 has been hypothesized as a contributor to the neuropsychiatric phenotypes. However, we show that Dlg1+/- mice did not exhibit the behavioral deficits seen in mice harboring the full 3q29 deletion. These data demonstrate the following: the 3q29 deletion mice are a valuable experimental system that can be used to interrogate the biology of 3q29 deletion syndrome; behavioral manifestations of the 3q29 deletion may have sex-dependent effects; and mouse-specific behavior phenotypes associated with the 3q29 deletion are not solely due to haploinsufficiency of Dlg1.

genetics↗

bioRxiv2018

TACAN is an essential component of the mechanosensitive ion channel responsible for pain sensing

Mechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying several physiological functions such as touch and pain sensing, hearing and proprioception. This process is carried out by specialized mechanosensitive ion channels whose identities have been discovered for most functions except pain sensing. Here we report the identification of TACAN (Tmem120A), an essential subunit of the mechanosensitive ion channel responsible for sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically-evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, knocking down TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to mechanical but not to thermal pain stimuli, without affecting the sensitivity to touch stimuli. We propose that TACAN is a pore-forming subunit of the mechanosensitive ion channel responsible for sensing mechanical pain.

neuroscience↗