Tracheal cytotoxin (TCT), a naturally occurring fragment of Gram-negative peptidoglycan, is a potent elicitor of innate immune responses in Drosophila. It induces the heterodimerization of its recognition receptors, the peptidoglycan recognition proteins (PGRPs) LCa and LCx, which activates the immune deficiency pathway. The crystal structure at 2.1 angstrom resolution of TCT in complex with the ectodomains of PGRP-LCa and PGRP-LCx shows that TCT is bound to and presented by the LCx ectodomain for recognition by the LCa ectodomain; the latter lacks a canonical peptidoglycan-docking groove conserved in other PGRPs. The interface, revealed in atomic detail, between TCT and the receptor complex highlights the importance of the anhydro-containing disaccharide in bridging the two ectodomains together and the critical role of diaminopimelic acid as the specificity determinant for PGRP interaction.

Situation Report-10 SITUATION IN NUMBERS Globally 7818 confirmed China 7736 confirmed 12167 suspected 1370 severe 170 deaths Outside of China 82 confirmed 18 countries WHO RISK ASSESSMENT China Very High Regional Level High Global Level High *The situation report includes information reported to WHO Geneva by 10 AM

No abstract

Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects. Conclusion: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer. (HEPATOLOGY 2014;59:974-985)

The Lon AAA+ protease (LonA) is an evolutionarily conserved protease that couples the ATPase cycle into motion to drive substrate translocation and degradation. A hallmark feature shared by AAA+ proteases is the stimulation of ATPase activity by substrates. Here we report the structure of LonA bound to three ADPs, revealing the first AAA+ protease assembly where the six protomers are arranged alternately in nucleotide-free and bound states. Nucleotide binding induces large coordinated movements of conserved pore loops from two pairs of three non-adjacent protomers and shuttling of the proteolytic groove between the ATPase site and a previously unknown Arg paddle. Structural and biochemical evidence supports the roles of the substrate-bound proteolytic groove in allosteric stimulation of ATPase activity and the conserved Arg paddle in driving substrate degradation. Altogether, this work provides a molecular framework for understanding how ATP-dependent chemomechanical movements drive allosteric processes for substrate degradation in a major protein-destruction machine.

The Lon AAA+ protease (LonA) plays important roles in protein homeostasis and regulation of diverse biological processes. LonA behaves as a homomeric hexamer in the presence of magnesium (Mg(2+)) and performs ATP-dependent proteolysis. However, it is also found that LonA can carry out Mg(2+)-dependent degradation of unfolded protein substrate in an ATP-independent manner. Here we show that in the presence of Mg(2+) LonA forms a non-secluded hexameric barrel with prominent openings, which explains why Mg(2+)-activated LonA can operate as a diffusion-based chambered protease to degrade unstructured protein and peptide substrates efficiently in the absence of ATP. A 1.85 Å crystal structure of Mg(2+)-activated protease domain reveals Mg(2+)-dependent remodeling of a substrate-binding loop and a potential metal-binding site near the Ser-Lys catalytic dyad, supported by biophysical binding assays and molecular dynamics simulations. Together, these findings reveal the specific roles of Mg(2+) in the molecular assembly and activation of LonA.

Background: Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD), and infection of EV71 to central nerve system (CNS) may result in a high mortality in children less than 2 years old. Although there are two highly glycosylated membrane proteins, SCARB2 and PSGL-1, which have been identified as the cellular and functional receptors of EV71, the role of glycosylation in EV71 infection is still unclear.

IntroductionAngiogenesis is involved in physiologic processes such as embryogenesis, wound healing, and the female reproductive cycle, and also contributes to the pathogenesis of numerous disorders, including atherosclerosis, ischemic disease, arthritis, and cancer. 1 Normally, angiogenesis is strictly controlled by the balance between angiogenic promoters and inhibitors.Thrombomodulin (TM) is a type I-glycosylated membrane protein composed of 5 distinct domains. At the NH 2 -terminal is a C-type lectin-like domain followed by 6 consecutively repeated epidermal growth factor (EGF)-like domains and an O-glycosylation site-rich domain. Connected to these extracellular domains is a transmembrane domain followed by a short cytoplasmic tail. 2 TM functions as part of the anticoagulant pathway; it binds thrombin on the cell surface and catalyzes proteolytic activation of protein C. 2 Soluble TM fragments have been detected in the medium of cultured TM-expressing cells 3 and human plasma and urine, 4-6 but the physiologic significance of the soluble TM fragments remains unclear. Our previous study showed that the recombinant EGF-like domain plus the O-glycosylation site-rich domain of TM (rTMD23) promotes angiogenesis in vitro and in vivo. 7 The multiple mechanisms underlying the anti-inflammatory activity of the recombinant lectin-like domain of TM have been demonstrated recently. [8][9][10][11] Lewis Y Ag (LeY) belongs to the type II Lewis Ag family, which is structurally related to the determinants of the ABH blood group system. LeY is expressed on the cell membrane along with phospholipids, 12 EGF receptors, 13 and mucins, 14 and its soluble form is up-regulated in the synovial fluid of human angiogenic rheumatoid arthritis. 15 LeY has been suggested to be a participant in cell-cell interaction, 16 arthritis, 15 and cancer. 17 In addition, ablation in endothelial cells of fucosyltransferase I, which is crucial for generation of the precursor of type II Lewis Ag, resulted in defective tube formation, suggesting the role of LeY in endothelial cell-cell contacts. 18 Previously, we demonstrated that recombinant lectin-like domain of TM (rTMD1) suppressed lipopolysaccharide-induced inflammation through interaction with LeY-conjugated lipopolysaccharide. 11 However, the biologic significance of the interaction between rTMD1 and LeY on the endothelial cell surface has never been investigated. In this study, the biologic function of LeY on endothelial cells and the antiangiogenic function of rTMD1 were investigated. In addition, recombinant adeno-associated virus (AAV) expression vector carrying TMD1 (AAV-TMD1) resulted in efficient suppression of angiogenesis with a single injection of AAV in mice. An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance ...