scholarly journals Structural Mechanics of the Alpha-2-Macroglobulin Transformation

2021 ◽  
Author(s):  
Yasuhiro Arimura ◽  
Hironori Funabiki
Keyword(s):  
Immune System ◽  
Xenopus Laevis ◽  
Protease Inhibitor ◽  
Structural Transformation ◽  
Innate Immune System ◽  
Innate Immune ◽  
Structural Basis ◽  
Intermediate Form ◽  
Native Form ◽  
Bait Region

SummaryAlpha-2-Macroglobulin (A2M) is the critical pan-protease inhibitor of the innate immune system. When proteases cleave the A2M bait region, global structural transformation of the A2M tetramer is triggered to entrap the protease. The structural basis behind the cleavage-induced transformation and the protease entrapment remains unclear. Here, we report cryo-EM structures of native- and intermediate-forms of the Xenopus laevis egg A2M homolog (A2Moo or ovomacroglobulin) tetramer at 3.7-4.1 Å and 6.4 Å resolution, respectively. In the native A2Moo tetramer, two pairs of dimers arrange into a cross-like configuration with four 60 Å-wide bait-exposing grooves. Each bait in the native form threads into an aperture formed by three macroglobulin domains (MG2, MG3, MG6). The bait is released from the narrowed aperture in the induced protomer of the intermediate form. We propose that the intact bait region works as a “latch-lock” to block futile A2M transformation until its protease-mediated cleavage.

scholarly journals Molecular and Structural Basis of DNA Sensors in Antiviral Innate Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Ayesha Zahid ◽  
Hazrat Ismail ◽  
Bofeng Li ◽  
Tengchuan Jin
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Innate Immune System ◽  
Rna Polymerase Iii ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Structural Basis ◽  
Type I ◽  
Dna Sensors ◽  
Dna Sensing

DNA viruses are a source of great morbidity and mortality throughout the world by causing many diseases; thus, we need substantial knowledge regarding viral pathogenesis and the host’s antiviral immune responses to devise better preventive and therapeutic strategies. The innate immune system utilizes numerous germ-line encoded receptors called pattern-recognition receptors (PRRs) to detect various pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids, ultimately resulting in antiviral immune responses in the form of proinflammatory cytokines and type I interferons. The immune-stimulatory role of DNA is known for a long time; however, DNA sensing ability of the innate immune system was unraveled only recently. At present, multiple DNA sensors have been proposed, and most of them use STING as a key adaptor protein to exert antiviral immune responses. In this review, we aim to provide molecular and structural underpinnings on endosomal DNA sensor Toll-like receptor 9 (TLR9) and multiple cytosolic DNA sensors including cyclic GMP-AMP synthase (cGAS), interferon-gamma inducible 16 (IFI16), absent in melanoma 2 (AIM2), and DNA-dependent activator of IRFs (DAI) to provide new insights on their signaling mechanisms and physiological relevance. We have also addressed less well-understood DNA sensors such as DEAD-box helicase DDX41, RNA polymerase III (RNA pol III), DNA-dependent protein kinase (DNA-PK), and meiotic recombination 11 homolog A (MRE11). By comprehensive understanding of molecular and structural aspects of DNA-sensing antiviral innate immune signaling pathways, potential new targets for viral and autoimmune diseases can be identified.

scholarly journals Single Stranded DNA Immune Modulators with Unmethylated CpG Motifs: Structure and Molecular Recognition by Toll-Like Receptor 9

2019 ◽  
Vol 20 (11) ◽  
pp. 1060-1068 ◽  
Author(s):  
Krisztina Fehér
Keyword(s):  
Immune System ◽  
Crystal Structures ◽  
Innate Immune System ◽  
Structural Features ◽  
Innate Immune ◽  
Structural Basis ◽  
Toll Like Receptor ◽  
Immune Modulators ◽  
Cpg Motifs ◽  
Cpg Motif

Single stranded microbial DNA fragments with unmethylated deoxycytidylyldeoxyguanosine dinucleotide (CpG) motifs are interpreted as danger signals by the innate immune system via recognition by the Toll-like Receptor 9 (TLR9). Their synthetic analogues, Oligodeoxynucleotides (ODN) comprise a promising class of immune modulators with potential applications in the treatment of multiple diseases, such as cancer, autoimmune diseases or allergy. ODN molecules contain a core hexamer sequence, which is species specific consisting of GACGTT and AACGT for mouse and GTCGTT in humans. Assessment of structural features of different type of ODNs is highly challenging. NMR spectroscopic insights were gained for a short, single CpG motif containing ODN 1668. The structural basis of ODN recognition by TLR9 recently started to unravel as crystal structures of TLR9 orthologues in complex with ODN 1668 were solved. Systematic investigations of ODN sequences revealed that ODNs with a single CpG motif are capable of activating mouse TLR9, but two closely positioned CpG motifs are necessary for activation of human TLR9. Furthermore, longer ODNs with TCC and TCG sequences at the 5’ end were shown to activate TLR9 with higher efficiency. It was revealed that 5’-xCx motif containing short ODNs (sODN) are able to augment the immune response of short, single CpG containing ODNs, which are incapable of activating of TLR9 alone. All these observations pointed to the existence of a second binding site on TLR9, which was characterized in crystal structures that delivered further insights of the nucleic acid recognition of the innate immune system by TLR9.

scholarly journals Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Kristian Stødkilde ◽  
Morten Torvund-Jensen ◽  
Søren K. Moestrup ◽  
Christian B. F. Andersen
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Structural Basis
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