NF-κB, Molecular Target
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Nuclear factor kappa B (NF-κB) is the generic term for a family of dimeric eukaryotic transcription factors with a critical role in major cellular functions including the immune and inflammatory responses, cell proliferation and differentiation, and the control of cell survival. NF-κB is composed of members of the Rel family of DNA-binding proteins and includes the mammalian proteins RelA (or p65), RelB, cRel, p50, and p52 and the Drosophila proteins Dorsal, Dif, and Relish. These proteins form homo- or heterodimers that bind with different affinities to a consensus DNA sequence motif (called the κB site) consisting of the sequence 5’-GGGRNWYYCC-3’ in which R is a purine, W is an adenosine or a thymine, Y is a pyrimidine, and N is any base.
The ankyrin repeat motif is one of the most common protein-protein interaction domains. Ankyrin repeats are modules of about 33 amino acids repeated in tandem. They are found in a large number of proteins with diverse cellular functions such as transcriptional regulators, signal transducers, cell-cycle regulators, and cytoskeletal proteins.
Defensins are a group of antimicrobial and cytotoxic peptides made by immune cells. There are seven defensins in humans, six alpha-defensins, and one beta-defensin, which are involved in the innate immune defense at the surface of epithelia from the respiratory tract, the intestinal tract, or the urinary tract.
The IκB kinase (IKK) complex is a high-molecular-weight (600–900 Kd) multisubunit complex present in the cytosol of most cell types. It contains two highly homologous catalytic subunits, IKKα (or IKK1) and IKKβ (or IKK2) that are serine/threonine protein kinases. They are structurally related and contain an amino-terminal kinase domain, a central leucine zipper region required for their dimerization and a carboxyl-terminal helix-loop-helix domain, which mediates protein interaction. The catalytic subunits interact through their carboxyl-terminal end with the third subunit, IKKγ (or NEMO for NF-κB essential modulator). IKKγ is the regulatory subunit of the IKK complex. It is structurally composed of protein-protein interaction motifs including two coiled-coiled domains, a leucine-zipper domain and a zinc-finger domain. IKKγ is essential for the structural organization and stability of the complex. IKKγ also has a regulatory function as it connects the IKK complex to potential upstream activators.
Matrix metalloproteinases (MMPs) also called metalloproteases, zinc endopeptidases, or matrixins are the largest and most diverse of the four groups of proteases. They are zinc-dependent, calcium-activated proteases synthesized as inactive precursors (or zymogens), which are proteolytically cleaved to generate the active enzyme. All matrixins contain an N-terminal peptide and a zinc-binding catalytic active site. The N-terminal peptide, which is cleaved during the activation step, contains a conserved motif, the cysteine switch whose cysteine residue chelates the zinc of the active site, rendering the enzyme inactive. MMPs degrade components of the extracellular matrix such as collagen and participate in several cellular processes including tissue remodeling, wound healing, angiogenesis, and tumor invasion.
Pathogen-associated molecular patterns (PAMPs) are microbial components derived from pathogens such as bacteria, viruses, fungi, and parasites. PAMPs are specifically recognized by the Toll-like receptors (TLRs), which are expressed by cells of the innate immune defense such as dendritic cells and macrophages. PAMPs comprise for very diverse components including lipopolysaccharide (LPS) from Gram-negative bacteria, lipoproteins and lipopeptides, flagellin, and bacterial and viral unmethylated CpG DNA or double-stranded RNA (dsRNA) produced by most replicating viruses.
Phosphorylation is the reversible process of introducing a phosphate group onto a protein. Phosphorylation occurs on the hydroxyamino acids serine and threonine or on tyrosine residues targeted by Ser/Thr kinases and tyrosine kinases, respectively. Dephosphorylation is catalyzed by phosphatases. Phosphorylation is a key mechanism for rapid posttranslational modulation of protein function. It is widely exploited in cellular processes to control various aspects of cell signaling, cell proliferation, cell differentiation, cell survival, cell metabolism, cell motility, and gene transcription.
Pattern recognition receptors (PRRs) are receptors expressed by cells from the innate immune system acting as sensors to rapidly detect invading pathogens. PRRs recognize conserved pathogen-associated molecular patterns (PAMPs) and distinguish foreign organisms such as bacteria, viruses, fungi, or parasites, from cells of the host. PRRs are divided into three families. The most studied family is the Toll-like receptors (TLRs). TLRs are membrane proteins anchored in the plasma membrane or at the surface of endosomes. TLRs are characterized by a common ligand-binding domain, which is composed of leucine-rich repeats (LRRs). Their recognition of either extracellular pathogens or PAMPs present in endosomes activates the innate and adaptive immune responses through signaling cascades controlling selective activation of NF-κB and other inducible transcription factors. The other two families of PRRs, the NOD-like receptors (NLRs) and the RIG-like helicases (RLHs) are soluble receptors present in the cytosol and act as sensors to detect a variety of viral and bacterial products. NOD1 and NOD2 (two NLRs) detect bacterial peptidoglycan, while the retinoic acid-inducible gene-1 (RIG-1) and the melanoma differentiation-associated gene-5 (MDA-5) are RNA helicases that sense viral double-stranded RNA (dsRNA).
The Rel homology domain (RHD) is an evolutionarily conserved domain found in some eukaryotic transcription factors, including NF-κB, the nuclear factors of activated T cells (NFATs), and the Drosophila proteins Dif and Relish. Some of these transcription factors form multiprotein DNA-bound complexes. Phosphorylation of the RHD appears to play a role in the regulation of the activity of some of these transcription factors and modulation of expression of their target genes. Structurally, the RHD is composed of two immunoglobulin-like-beta-barrel subdomains that grip the DNA in the major groove. The amino-terminal portion of the RHD contains a recognition loop that directly interacts with DNA bases. The carboxyl-terminal portion of the NF-κB RHD contains the site for interaction with the IκBs.
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