Zeyaul Islam

Hamad bin Khalifa University

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Prasanna R. Kolatkar

Hamad bin Khalifa University

Munazza Fatima

Islamia University of Bahawalpur

Omar M. A. El‐Agnaf

Hamad bin Khalifa University

Issam Hmila

Hamad bin Khalifa University

Nishant N. Vaikath

Hamad bin Khalifa University

Sandra Martha Gomes Dias

Brazilian Center for Research in Energy and Materials

Indulekha P. Sudhakaran

Hamad bin Khalifa University

Parveen Salahuddin

Aligarh Muslim University

Vijay Gupta

Scripps Research Institute

Rizwan Hasan Khan

Aligarh Muslim University

Cooperative Institutions

Hamad bin Khalifa University

Qatar Foundation

Brazilian Center for Research in Energy and Materials

Brazilian Biosciences National Laboratory

Laboratório Nacional de Ciência e Tecnologia do Bioetanol

Universidade Estadual de Campinas (UNICAMP)

Universidade de São Paulo

Qatar Airways (Qatar)

Qatar University

Inserm

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Sox2: A Regulatory Factor in Tumorigenesis and Metastasis

Current Protein and Peptide Science (2019)

Sameer Chaudhary Zeyaul Islam Vijaya Mishra Sakshi Rawat Ghulam Md Ashraf

The transcription factor Sox2 plays an important role in various phases of embryonic development, including cell fate and differentiation. These key regulatory functions are facilitated by binding to specific DNA sequences in combination with partner proteins to exert their effects. Recently, overexpression and gene amplification of Sox2 has been associated with tumor aggression and metastasis in various cancer types, including breast, prostate, lung, ovarian and colon cancer. All the different roles for Sox2 involve complicated regulatory networks consisting of protein-protein and protein-nucleic acid interactions. Their involvement in the EMT modulation is possibly enabled by Wnt/ β-catenin and other signaling pathways. There are number of in vivo models which show Sox2 association with increased cancer aggressiveness, resistance to chemo-radiation therapy and decreased survival rate suggesting Sox2 as a therapeutic target. This review will focus on the different roles for Sox2 in metastasis and tumorigenesis. We will also review the mechanism of action underlying the cooperative Sox2- DNA/partner factors binding where Sox2 can be potentially explored for a therapeutic opportunity to treat cancers.

10.2174/1389203720666190325102255

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Citations (52)

Additional file 1: of Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

Figshare (2019)

Hyung‐Goo Kim Jill A. Rosenfeld Daryl A. Scott Gerard BĂŠnĂŠdicte Jonathan D. J. Labonne

List of 520 genes in the intellectual disability panel. (XLSX 17 kb)

Craniofacial abnormality

10.6084/m9.figshare.10027709

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Citations (0)

Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies

International Journal of Biological Macromolecules (2021)

Parveen Salahuddin Rizwan Hasan Khan Mohammad Furkan Vladimir N. Uversky Zeyaul Islam

Amyloid (mycology)

Oligomer

10.1016/j.ijbiomac.2021.07.056

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Citations (38)

Expression, purification, crystallization and preliminary X-ray analysis of maleylacetate reductase fromBurkholderiasp. strain SJ98

Acta Crystallographica Section F Structural Biology and Crystallization Communications (2009)

Archana Chauhan Zeyaul Islam Rakesh Jain Subramanian Karthikeyan

Maleylacetate reductase (EC 1.3.1.32) is an important enzyme that is involved in the degradation pathway of aromatic compounds and catalyzes the reduction of maleylacetate to 3-oxoadipate. The gene pnpD encoding maleylacetate reductase in Burkholderia sp. strain SJ98 was cloned, expressed in Escherichia coli and purified by affinity chromatography. The enzyme was crystallized in both native and SeMet-derivative forms by the sitting-drop vapour-diffusion method using PEG 3350 as a precipitant at 293 K. The crystals belonged to space group P21212, with unit-cell parameters a = 72.91, b = 85.94, c = 53.07 Å. X-ray diffraction data for the native and SeMet-derivative crystal were collected to 2.7 and 2.9 Å resolution, respectively.

Strain (injury)

Derivative (finance)

10.1107/s1744309109047319

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Citations (1)

Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism

Molecular Autism (2019)

Hyung‐Goo Kim Jill A. Rosenfeld Daryl A. Scott Gerard Bénédicte Jonathan D. J. Labonne

Abstract Background PHF21A has been associated with intellectual disability and craniofacial anomalies based on its deletion in the Potocki-Shaffer syndrome region at 11p11.2 and its disruption in three patients with balanced translocations. In addition, three patients with de novo truncating mutations in PHF21A were reported recently. Here, we analyze genomic data from seven unrelated individuals with mutations in PHF21A and provide detailed clinical descriptions, further expanding the phenotype associated with PHF21A haploinsufficiency. Methods Diagnostic trio whole exome sequencing, Sanger sequencing, use of GeneMatcher, targeted gene panel sequencing, and MiSeq sequencing techniques were used to identify and confirm variants. RT-qPCR was used to measure the normal expression pattern of PHF21A in multiple human tissues including 13 different brain tissues. Protein-DNA modeling was performed to substantiate the pathogenicity of the missense mutation. Results We have identified seven heterozygous coding mutations, among which six are de novo (not maternal in one). Mutations include four frameshifts, one nonsense mutation in two patients, and one heterozygous missense mutation in the AT Hook domain, predicted to be deleterious and likely to cause loss of PHF21A function. We also found a new C-terminal domain composed of an intrinsically disordered region. This domain is truncated in six patients and thus likely to play an important role in the function of PHF21A, suggesting that haploinsufficiency is the likely underlying mechanism in the phenotype of seven patients. Our results extend the phenotypic spectrum of PHF21A mutations by adding autism spectrum disorder, epilepsy, hypotonia, and neurobehavioral problems. Furthermore, PHF21A is highly expressed in the human fetal brain, which is consistent with the neurodevelopmental phenotype. Conclusion Deleterious nonsense, frameshift, and missense mutations disrupting the AT Hook domain and/or an intrinsically disordered region in PHF21A were found to be associated with autism spectrum disorder, epilepsy, hypotonia, neurobehavioral problems, tapering fingers, clinodactyly, and syndactyly, in addition to intellectual disability and craniofacial anomalies. This suggests that PHF21A is involved in autism spectrum disorder and intellectual disability, and its haploinsufficiency causes a diverse neurological phenotype.

Haploinsufficiency

Sanger sequencing

Human genetics

Exome

Loss function

Nonsense mutation

10.1186/s13229-019-0286-0

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Citations (40)

Ribonucleoprotein particles containing heterogeneous nuclear RNA

Elsevier eBooks (1986)

John T. Knowler C.W. McGregor Zeyaul Islam

Heterogeneous nuclear ribonucleoprotein

10.1016/b978-0-407-00323-1.50013-3

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Citations (3)

Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12

Cell Death and Disease (2023)

Kripa S Keyan Safa Salim Swetha B. M. Gowda Doua Abdelrahman Syeda Sakina Amir

Transforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFβ signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFβ signalling in multiple models. Interestingly, TRIP12 control of TGFβ signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFβ signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFβ signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFβ mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFβ induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFβ signalling in health and disease.

Genetic screen

10.1038/s41419-023-06215-y

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Expression, purification and characterization of α-synuclein fibrillar specific scFv from inclusion bodies

PLoS ONE (2020)

Vijay Gupta Indulekha P. Sudhakaran Zeyaul Islam Nishant N. Vaikath Issam Hmila

Aggregation of α-synuclein (α-syn) has been implicated in multiple neurodegenerative disorders including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), collectively grouped as synucleinopathies. Recently, recombinant antibody fragments (Fab, scFvs and diabodies) against α-syn have emerged as an alternative to the traditional full-length antibody in immunotherapeutic approaches owing to their advantages including smaller size and higher stability, specificity and affinity. However, most of the recombinant antibody fragments tend to be expressed as inclusion bodies (IBs) making its purification extremely challenging. In the current study, a single-chain variable fragment (scFv-F) antibody, targeting the pathogenic α-syn fibrils, was engineered and expressed in E. coli. Majority of the expressed scFv-F accumulated in insoluble aggregates as IBs. A variety of mild and harsh solubilizing conditions were tested to solubilize IBs containing scFv-F to obtain the active protein. To preserve secondary structure and bioactivity, a mild solubilizing protocol involving 100 mM Tris, pH 12.5 with 2 M urea was chosen to dissolve IBs. Slow on-column refolding method was employed to subsequently remove urea and obtain active scFv-F. A three-dimensional (3D) model was built using homology modeling and subjected to molecular docking with the known α-syn structure. Structural alignment was performed to delineate the potential binding pocket. The scFv-F thus purified demonstrated high specificity towards α-syn fibrils compared to monomers. Molecular modeling studies suggest that scFv-F shares the same structural topology with other known scFvs. We present evidence through structural docking and alignment that scFv-F binds to α-syn C-terminal region. In conclusion, mild solubilization followed by slow on-column refolding can be utilized as a generalized and efficient method for hard to purify disease relevant insoluble proteins and/or antibody molecules from IBs.

Synucleinopathies

Inclusion bodies

Docking (animal)

10.1371/journal.pone.0241773

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Citations (9)

Nanoparticle formulations in the diagnosis and therapy of Alzheimer's disease

International Journal of Biological Macromolecules (2019)

Jyoti Gupta Munazza Fatima Zeyaul Islam Rizwan Hasan Khan Vladimir N. Uversky

Transcytosis

Transcellular

Paracellular transport

10.1016/j.ijbiomac.2019.02.156

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Citations (125)

Structural Basis for Competitive Inhibition of 3,4-Dihydroxy-2-butanone-4-phosphate Synthase from Vibrio cholerae

Journal of Biological Chemistry (2015)

Zeyaul Islam Adarsh Kumar Suruchi Singh L. Salmon Subramanian Karthikeyan

The riboflavin biosynthesis pathway has been shown to be essential in many pathogens and is absent in humans. Therefore, enzymes involved in riboflavin synthesis are considered as potential antibacterial drug targets. The enzyme 3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS) catalyzes one of the two committed steps in the riboflavin pathway and converts d-ribulose 5-phosphate (Ru5P) to l-3,4-dihydroxy-2-butanone 4-phosphate and formate. Moreover, DHBPS is shown to be indispensable for Mycobacterium, Salmonella, and Helicobacter species. Despite the essentiality of this enzyme in bacteria, no inhibitor has been identified hitherto. Here, we describe kinetic and crystal structure characterization of DHBPS from Vibrio cholerae (vDHBPS) with a competitive inhibitor 4-phospho-d-erythronohydroxamic acid (4PEH) at 1.86-Å resolution. In addition, we also report the structural characterization of vDHBPS in its apo form and in complex with its substrate and substrate plus metal ions at 1.96-, 1.59-, and 2.04-Å resolution, respectively. Comparison of these crystal structures suggests that 4PEH inhibits the catalytic activity of DHBPS as it is unable to form a proposed intermediate that is crucial for DHBPS activity. Furthermore, vDHBPS structures complexed with substrate and metal ions reveal that, unlike Candida albicans, binding of substrate to vDHBPS induces a conformational change from an open to closed conformation. Interestingly, the position of second metal ion, which is different from that of Methanococcus jannaschii, strongly supports an active role in the catalytic mechanism. Thus, the kinetic and structural characterization of vDHBPS reveals the molecular mechanism of inhibition shown by 4PEH and that it can be explored further for designing novel antibiotics.

Lyase

Methanococcus

Hydrolase

10.1074/jbc.m114.611830

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Citations (18)