ORCID Profile
0000-0002-9112-2454
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Publisher: Springer Science and Business Media LLC
Date: 13-08-2021
Publisher: Oxford University Press (OUP)
Date: 03-02-2021
DOI: 10.1093/NAR/GKAA1287
Abstract: Interferon regulatory factor 4 (IRF4) is a key transcription factor (TF) in the regulation of immune cells, including B and T cells. It acts by binding DNA as both a homodimer and, in conjunction with other TFs, as a heterodimer. The choice of homo and heterodimeric/ DNA interactions is a critical aspect in the control of the transcriptional program and cell fate outcome. To characterize the nature of this interaction in the homodimeric complex, we have determined the crystal structure of the IRF4/ISRE homodimeric complex. We show that the complex formation is aided by a substantial DNA deformation with co-operative binding achieved exclusively through protein–DNA contact. This markedly contrasts with the heterodimeric form where DNA bound IRF4 is shown to physically interact with PU.1 TF to engage EICE1. We also show that the hotspot residues (Arg98, Cys99 and Asn102) contact both consensus and non-consensus sequences with the L1 loop exhibiting marked flexibility. Additionally, we identified that IRF4L116R, a mutant associated with chronic lymphocytic leukemia, binds more robustly to DNA thereby providing a rationale for the observed gain of function. Together, we demonstrate key structural differences between IRF4 homo and heterodimeric complexes, thereby providing molecular insights into IRF4-mediated transcriptional regulation.
Publisher: Elsevier BV
Date: 05-2018
Publisher: Proceedings of the National Academy of Sciences
Date: 19-01-2018
Abstract: MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 ersity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in CD1D1 −/− mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of α-galactosylceramide revealed that its A′-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells.
Publisher: Springer Science and Business Media LLC
Date: 28-03-2018
DOI: 10.1007/S12104-018-9818-3
Abstract: Ahnak is a ~ 700 kDa polypeptide that was originally identified as a tumour-related nuclear phosphoprotein, but later recognized to play a variety of erse physiological roles related to cell architecture and migration. A critical function of Ahnak is modulation of Ca
Publisher: Elsevier BV
Date: 07-2018
Publisher: Public Library of Science (PLoS)
Date: 03-04-2014
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.CECA.2021.102403
Abstract: The phosphoprotein AHNAK is a large, ubiquitously expressed scaffolding protein involved in mediating a host of protein-protein interactions. This enables AHNAK to participate in various multi-protein complexes thereby orchestrating a range of erse biological processes, including tumour suppression, immune regulation and cell architecture maintenance. A less studied but nonetheless equally important function occurs in calcium homeostasis. It does so by largely interacting with the L-type voltage-gated calcium channel (LVGCC) present in the plasma membrane of excitable cells such as muscles and neurons. Several studies have characterized the underlying basis of AHNAK's functional role in calcium channel modulation, which has led to a greater understanding of this cellular process and its associated pathologies. In this article we review and examine recent advances relating to the physiological aspects of AHNAK in calcium regulation. Specifically, we will provide a broad overview of AHNAK including its structural makeup and its interaction with several isoforms of LVGCC, and how these molecular interactions regulate calcium modulation across various tissues and their implication in muscle and neuronal function.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CELREP.2019.08.072
Abstract: The NLRP3 inflammasome is a cytosolic complex sensing phagocytosed material and various damage-associated molecular patterns, triggering production of the pro-inflammatory cytokines interleukin-1 beta (IL)-1β and IL-18 and promoting pyroptosis. Here, we characterize glutathione transferase omega 1-1 (GSTO1-1), a constitutive deglutathionylating enzyme, as a regulator of the NLRP3 inflammasome. Using a small molecule inhibitor of GSTO1-1 termed C1-27, endogenous GSTO1-1 knockdown, and GSTO1-1
Publisher: Public Library of Science (PLoS)
Date: 16-10-2012
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.BMC.2013.05.052
Abstract: Self-assembled peptide based nanostructures gained enough popularity due to their easy biocompatibility and numerous potential applications. An excellent model of self-assembly of hydroxyethylamine based peptide nanostructures was synthesized and characterized by DLS and TEM. Spherical nano structures of I and III were observed with particle size ∼50 and ∼80nm, respectively. Further, I and III were screened against anti-malarial target, falcipain-3 (FP3), a crucial cysteine protease involved as a major hemoglobinase of Plasmodium falciparum. Interestingly, compound III completely inhibited the activity of FP3. The effective concentration (1.5μM) of III found to be more potent than I. This biochemical result was substantiated by molecular-docking studies indicating III to be best inhibitor of FP3. This is the first report showing that bis hydroxethylamine based peptide nanostructures could be very effective inhibitor of malarial cysteine proteases.
Publisher: Wiley
Date: 15-02-2022
DOI: 10.1002/PRO.4260
Abstract: Interferon regulatory factor 4 (IRF4) is an essential regulator in the development of many immune cells, including B‐ and T‐cells and has been implicated directly in numerous hematological malignancies, including adult T‐cell leukemia/lymphoma (ATLL). Recently, an activating mutation in the DNA‐binding domain of IRF4 (IRF4 K59R ) was found as a recurrent somatic mutation in ATLL patients. However, it remains unknown how this mutation gives rise to the observed oncogenic effect. To understand the mode of IRF4 K59R ‐mediated gain of function in ATLL pathogenesis, we have determined the structural and affinity basis of IRF4 K59R /DNA homodimer complex using X‐ray crystallography and surface plasmon resonance. Our study shows that arginine substitution (R59) results in the reorientation of the side chain, enabling the guanidium group to interact with the phosphate backbone of the DNA helix. This markedly contrasts with the IRF4 WT wherein the K59 interacts exclusively with DNA bases. Further, the arginine mutation causes enhanced DNA bending, enabling the IRF4 K59R to interact more robustly with known DNA targets, as evidenced by increased binding affinity of the protein–DNA complex. Together, we demonstrate how key structural features underpin the basis for this activating mutation, thereby providing a molecular rationale for IRF4 K59R ‐mediated ATLL development.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2019
DOI: 10.1038/S41467-019-12941-9
Abstract: Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that erse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.
No related grants have been discovered for Srinivasan sundararaj.