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Dive into the research topics where Syed R. Ali is active.

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Featured researches published by Syed R. Ali.


Journal of Biological Chemistry | 2008

Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Stephanie Konrad; Syed R. Ali; Kristina Wiege; Shahzad N. Syed; Linda Engling; Roland P. Piekorz; Emilio Hirsch; Bernd Nürnberg; Reinhold Schmidt; J. Engelbert Gessner

Fcγ receptors (FcγR) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in IC-induced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3Kγ abrogates C5aR signaling that is crucial for FcγR-mediated activation of lung macrophages. Thus, in PI3Kγ-/- mice, IgG IC-induced FcγR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kγ-/- mice but was impaired in PI3Kδ-/- mice. Consequently, class IA PI3Kδ deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kγ and PI3Kδ coordinate the inflammatory effects of C5aR and FcγR and define PI3Kδ as a novel and essential element of FcγR signaling in the generation of C5a in IC disease.


Journal of Biological Chemistry | 2008

PI3Kgamma and PI3Kdelta: Linkers of coordinate C5aR-FcgammaR activation and immune complex-induced inflammation

Stephanie Konrad; Syed R. Ali; Kristina Wiege; Shahzad N. Syed; Linda Engling; Roland P. Piekorz; Emilio Hirsch; Bernd Nürnberg; Reinhold Schmidt; J. Engelbert Gessner

Fcγ receptors (FcγR) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in IC-induced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3Kγ abrogates C5aR signaling that is crucial for FcγR-mediated activation of lung macrophages. Thus, in PI3Kγ-/- mice, IgG IC-induced FcγR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kγ-/- mice but was impaired in PI3Kδ-/- mice. Consequently, class IA PI3Kδ deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kγ and PI3Kδ coordinate the inflammatory effects of C5aR and FcγR and define PI3Kδ as a novel and essential element of FcγR signaling in the generation of C5a in IC disease.


Molecular & Cellular Proteomics | 2015

Quantitative Proteomics Reveals Protein–Protein Interactions with Fibroblast Growth Factor 12 as a Component of the Voltage-Gated Sodium Channel 1.2 (Nav1.2) Macromolecular Complex in Mammalian Brain

Norelle C. Wildburger; Syed R. Ali; Wei Chun J Hsu; Alexander S. Shavkunov; Miroslav N. Nenov; Cheryl F. Lichti; Richard D. LeDuc; Ekaterina Mostovenko; Neli I. Panova-Elektronova; Mark R. Emmett; Carol L. Nilsson; Fernanda Laezza

Voltage-gated sodium channels (Nav1.1–Nav1.9) are responsible for the initiation and propagation of action potentials in neurons, controlling firing patterns, synaptic transmission and plasticity of the brain circuit. Yet, it is the protein–protein interactions of the macromolecular complex that exert diverse modulatory actions on the channel, dictating its ultimate functional outcome. Despite the fundamental role of Nav channels in the brain, information on its proteome is still lacking. Here we used affinity purification from crude membrane extracts of whole brain followed by quantitative high-resolution mass spectrometry to resolve the identity of Nav1.2 protein interactors. Of the identified putative protein interactors, fibroblast growth factor 12 (FGF12), a member of the nonsecreted intracellular FGF family, exhibited 30-fold enrichment in Nav1.2 purifications compared with other identified proteins. Using confocal microscopy, we visualized native FGF12 in the brain tissue and confirmed that FGF12 forms a complex with Nav1.2 channels at the axonal initial segment, the subcellular specialized domain of neurons required for action potential initiation. Co-immunoprecipitation studies in a heterologous expression system validate Nav1.2 and FGF12 as interactors, whereas patch-clamp electrophysiology reveals that FGF12 acts synergistically with CaMKII, a known kinase regulator of Nav channels, to modulate Nav1.2-encoded currents. In the presence of CaMKII inhibitors we found that FGF12 produces a bidirectional shift in the voltage-dependence of activation (more depolarized) and the steady-state inactivation (more hyperpolarized) of Nav1.2, increasing the channel availability. Although providing the first characterization of the Nav1.2 CNS proteome, we identify FGF12 as a new functionally relevant interactor. Our studies will provide invaluable information to parse out the molecular determinant underlying neuronal excitability and plasticity, and extending the relevance of iFGFs signaling in the normal and diseased brain.


Journal of Biological Chemistry | 2011

Human Siglec-5 Inhibitory Receptor and Immunoglobulin A (IgA) Have Separate Binding Sites in Streptococcal {beta} Protein.

Therése Nordström; Elin Movert; Anders I. Olin; Syed R. Ali; Victor Nizet; Ajit Varki; Thomas Areschoug

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors believed to be important for regulation of cellular activation and inflammation. Several pathogenic microbes bind specific Siglecs via sialic acid-containing structures at the microbial surface, interactions that may result in modulation of host responses. Recently, it was shown that the group B Streptococcus (GBS) binds to human Siglec-5 (hSiglec-5), an inhibitory receptor expressed on macrophages and neutrophils, via the IgA-binding surface β protein, providing the first example of a protein/protein interaction between a pathogenic microbe and a Siglec. Here we show that the hSiglec-5-binding part of β resides in the N-terminal half of the protein, which also harbors the previously determined IgA-binding region. We constructed bacterial mutants expressing variants of the β protein with non-overlapping deletions in the N-terminal half of the protein. Using these mutants and recombinant β fragments, we showed that the hSiglec-5-binding site is located in the most N-terminal part of β (B6N region; amino acids 1–152) and that the hSiglec-5- and IgA-binding domains in β are completely separate. We showed with BIAcoreTM analysis that tandem variants of the hSiglec-5- and IgA-binding domains bind to their respective ligands with high affinity. Finally, we showed that the B6N region, but not the IgA-binding region of β, triggers recruitment of the tyrosine phosphatase SHP-2 to hSiglec-5 in U937 monocytes. Taken together, we have identified and isolated the first microbial non-sialic acid Siglec-binding region that can be used as a tool in studies of the β/hSiglec-5 interaction.


Cns & Neurological Disorders-drug Targets | 2014

Modulation of the FGF14:FGF14 homodimer interaction through short peptide fragments.

Syed R. Ali; Alexander S. Shavkunov; Neli Panova; Svetla Stoilova-McPhie; Fernanda Laezza

Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGF (iFGFs) family and a functionally relevant component of the neuronal voltage-gated Na(+) (Nav) channel complex. Through a monomeric interaction with the intracellular C-terminus of neuronal Nav channels, FGF14 modulates Na(+) currents in an Nav isoform-specific manner serving as a fine-tuning regulator of excitability. Previous studies based on the highly homologous FGF13 homodimer crystal structure have proposed a conserved protein:protein interaction (PPI) interface common to both Nav channel binding and iFGF homodimer formation. This interface could provide a novel target for drug design against neuronal Nav channels. Here, we provide the first in-cell reconstitution of the FGF14:FGF14 protein complex and measure the dimer interaction using the split-luciferase complementation assay (LCA). Based on the FGF14 dimer structure generated in silico, we designed short peptide fragments against the FGF14 dimer interface. One of these fragments, FLPK aligns with the pocket defined by the β12-strand and β8-β9 loop, reducing the FGF14:FGF14 dimer interaction by 25% as measured by LCA. We further compared the relative interaction strength of FGF14 wild type homodimers with FGF14 hetero- and homodimers carrying double N mutations at the Y153 and V155 residues, located at the β8-β9 loop. The Y153N/V155N double mutation counteracts the FLPK effect by increasing the strength of the dimer interaction. These data suggest that the β12 strand of FGF14 might serve as scaffold for drug design against neuronal FGF14 dimers and Nav channels.


Methods of Molecular Biology | 2015

Split-luciferase complementation assay to detect channel-protein interactions in live cells.

Alexander S. Shavkunov; Syed R. Ali; Neli I. Panova-Elektronova; Fernanda Laezza

The understanding of ion channel function continues to be a significant driver in molecular pharmacology. In this field of study, protein-protein interactions are emerging as fundamental molecular determinants of ion channel function and as such are becoming an attractive source of highly specific targets for drug development. The investigation of ion channel macromolecular complexes, however, still relies on conventional methods that are usually technically challenging and time-consuming, significantly hampering our ability to identify, characterize and modify ion channel function through targeted molecular approaches. As a response to the urgent need of developing rapid and albeit accurate technologies to survey ion channel molecular complexes, we describe a new application of the split-luciferase complementation assay to study the interaction of the voltage-gated Na + channel with the intracellular fibroblast growth factor 14 and its dynamic regulation in live cells. We envision that the flexibility and accessibility of this assay will have a broad impact in the ion channel field complementing structural and functional studies, enabling the interrogation of protein-channel dynamic interactions in complex cellular contexts and laying the basis for new frameworks in drug discovery campaigns.


Immunology and Cell Biology | 2017

Tamm–Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract

Kathryn A. Patras; Alison Coady; Joshua Olson; Syed R. Ali; Satish P RamachandraRao; Satish Kumar; Ajit Varki; Victor Nizet

Urinary tract infections are a major problem in human medicine for which better understanding of native immune defenses may reveal new pathways for therapeutic intervention. Tamm–Horsfall glycoprotein (THP), the most abundant urinary protein, interacts with bacteria including uropathogenic Escherichia coli (UPEC) as well host immune cells. In addition to its well‐studied functions to antagonize bacterial colonization, we hypothesize that THP serves a critical host defense function through innate immune modulation. Using isolated human neutrophils, we found that THP binds neutrophils and that this interaction reduces reactive oxygen species generation, chemotaxis and killing of UPEC. We discovered that THP engages the inhibitory neutrophil receptor sialic acid‐binding Ig‐like lectin‐9 (Siglec‐9), and mouse functional ortholog Siglec‐E, in a manner dependent on sialic acid on its N‐glycan moieties. THP‐null mice have significantly more neutrophils present in the urine compared with wild‐type mice, both with and without the presence of inflammatory stimuli. These data support THP as an important negative regulator of neutrophil activation in the urinary tract, with dual functions to counteract bacterial colonization and suppress excessive inflammation within the urinary tract.


Journal of Biological Chemistry | 2016

Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6

Syed R. Ali; Aditya K. Singh; Fernanda Laezza

The voltage-gated Na+ (Nav) channel provides the basis for electrical excitability in the brain. This channel is regulated by a number of accessory proteins including fibroblast growth factor 14 (FGF14), a member of the intracellular FGF family. In addition to forming homodimers, FGF14 binds directly to the Nav1.6 channel C-tail, regulating channel gating and expression, properties that are required for intrinsic excitability in neurons. Seeking amino acid residues with unique roles at the protein-protein interaction interface (PPI) of FGF14·Nav1.6, we engineered model-guided mutations of FGF14 and validated their impact on the FGF14·Nav1.6 complex and the FGF14:FGF14 dimer formation using a luciferase assay. Divergence was found in the β-9 sheet of FGF14 where an alanine (Ala) mutation of Val-160 impaired binding to Nav1.6 but had no effect on FGF14:FGF14 dimer formation. Additional analysis revealed also a key role of residues Lys-74/Ile-76 at the N-terminal of FGF14 in the FGF14·Nav1.6 complex and FGF14:FGF14 dimer formation. Using whole-cell patch clamp electrophysiology, we demonstrated that either the FGF14V160A or the FGF14K74A/I76A mutation was sufficient to abolish the FGF14-dependent regulation of peak transient Na+ currents and the voltage-dependent activation and steady-state inactivation of Nav1.6; but only V160A with a concomitant alanine mutation at Tyr-158 could impede FGF14-dependent modulation of the channel fast inactivation. Intrinsic fluorescence spectroscopy of purified proteins confirmed a stronger binding reduction of FGF14V160A to the Nav1.6 C-tail compared with FGF14K74A/I76A. Altogether these studies indicate that the β-9 sheet and the N terminus of FGF14 are well positioned targets for drug development of PPI-based allosteric modulators of Nav channels.


ACS Chemical Neuroscience | 2018

Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic

Syed R. Ali; Zhiqing Liu; Miroslav N. Nenov; Oluwarotimi Folorunso; Aditya K. Singh; Federico Scala; Haiying Chen; Thomas F. James; Musaad A. Alshammari; Neli I. Panova-Elektronova; Mark A. White; Jia Zhou; Fernanda Laezza

Protein-protein interactions (PPI) offer unexploited opportunities for CNS drug discovery and neurochemical probe development. Here, we present ZL181, a novel peptidomimetic targeting the PPI interface of the voltage-gated Na+ channel Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). ZL181 binds to FGF14 and inhibits its interaction with the Nav1.6 channel C-tail. In HEK-Nav1.6 expressing cells, ZL181 acts synergistically with FGF14 to suppress Nav1.6 current density and to slow kinetics of fast inactivation, but antagonizes FGF14 modulation of steady-state inactivation that is regulated by the N-terminal tail of the protein. In medium spiny neurons in the nucleus accumbens, ZL181 suppresses excitability by a mechanism that is dependent upon expression of FGF14 and is consistent with a state-dependent inhibition of FGF14. Overall, ZL181 and derivatives could lay the ground for developing allosteric modulators of Nav channels that are of interest for a broad range of CNS disorders.


Austin journal of pharmacology and therapeutics | 2013

Protein-Protein Interactions as New Targets for Ion Channel Drug Discovery.

Svetla Stoilova-McPhie; Syed R. Ali; Fernanda Laezza

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Fernanda Laezza

University of Texas Medical Branch

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Aditya K. Singh

University of Tennessee Health Science Center

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Svetla Stoilova-McPhie

University of Texas Medical Branch

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Alexander S. Shavkunov

University of Texas Medical Branch

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Jia Zhou

University of Texas Medical Branch

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Miroslav N. Nenov

University of Texas Medical Branch

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Neli I. Panova-Elektronova

University of Texas Medical Branch

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Zhiqing Liu

University of Texas Medical Branch

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Ajit Varki

University of California

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Haiying Chen

University of Texas Medical Branch

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