trigolactones (SLs) are plant hormones that play an essential role in the regulation of various developmental processes including shoot branching and root architecture. SLs also act as rhizospheric-secreted signals facilitating communication with symbiotic fungi and parasitic plants [1][2][3][4][5][6] . The activation of several signalling cascades governed by plant hormones involves the action of E3 ubiquitin (Ub) ligase enzymes that coordinate specific targeting and degradation of transcriptional repressors 7 . Genetic and biochemical studies showed that SLs are perceived by the α/β-hydrolase receptor DWARF14 (D14) 8,9 that interacts with the E3 Ub ligase DWARF3/MORE AXILLARY BRANCHES2 (D3/MAX2) 2,10 to target DWARF53 (D53)/SUPPRESSOR OF MAX2-LIKE 6, -7 and -8 (SMXL6/7/8) by ubiquitination and subsequent degradation via the 26S proteasome [11][12][13] . D3/MAX2 is a leucine-rich repeat (LRR)-type F-box protein that binds Arabidopsis (At) SKP1-like protein (ASK1) to function as a substrate receptor of an SKP1-CUL1-F-box (SCF) Ub ligase complex 2 . D53/SMXLs proteins have weak similarity to AAA+ ATPase proteins, contain transcriptional repression EAR motifs, and are rapidly degraded following SL treatment [12][13][14][15] . About 400 SL-responsive genes were identified in an Arabidopsis transcriptome analysis following synthetic SL treatment, and SMXL6 was found to function as an autoregulator by directly binding SMXL6, SMXL7 and SMXL8 promoters 16 .Coupled with genetic findings, structural biology studies have deepened our understanding of signalling mechanisms for several plant hormones such as auxin (AUX) and jasmonate. These two hormones are directly perceived by their E3 ligases, TIR1 and COI1 respectively, and facilitate the interaction of the E3 ligase with its target protein (auxin/indole-3-acetic acid (AUX/IAA) or JASMONATE ZIM-DOMAIN (JAZ)) [17][18][19] . In striking contrast, SL perception and signalling exhibit more complex non-binary interactions between the D14 hydrolase (the SL receptor), SCF D3/MAX2 (the E3 ligase) and equal variance by F-tests. No statistical methods were used to predetermine sample size. All pulldown and in vitro degradation assays were repeated independently three times with similar results.
Cryptochromes (CRYs) are evolutionarily conserved photoreceptors that mediate various light-induced responses in bacteria, plants, and animals. Plant cryptochromes govern a variety of critical growth and developmental processes including seed germination, flowering time and entrainment of the circadian clock. CRY’s photocycle involves reduction of their flavin adenine dinucleotide (FAD)-bound chromophore, which is completely oxidized in the dark and semi to fully reduced in the light signaling-active state. Despite the progress in characterizing cryptochromes, important aspects of their photochemistry, regulation, and light-induced structural changes remain to be addressed. In this study, we determine the crystal structure of the photosensory domain of Arabidopsis CRY2 in a tetrameric active state. Systematic structure-based analyses of photo-activated and inactive plant CRYs elucidate distinct structural elements and critical residues that dynamically partake in photo-induced oligomerization. Our study offers an updated model of CRYs photoactivation mechanism as well as the mode of its regulation by interacting proteins.
The ERK1/2 signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins such as Shoc2 to guide and fine-tune its signals. Mutations in shoc2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We identify that in the Shoc2 module USP7 functions as a molecular “switch” that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop. We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.
Cryptochromes (CRYs) are evolutionarily conserved blue-light receptors that mediate various light-induced responses in bacteria, plants, and animals. Plant cryptochromes govern a variety of critical growth and developmental processes including seed germination, flowering time and entrainment of the circadian clock. CRYs photocycle involves reduction of their flavin adenine dinucleotide (FAD)-bound chromophore, which is completely oxidized in the dark and semireduced in the light signalling-active state. Despite the significant progress in characterizing cryptochromes, important aspects of their photochemistry, regulation, and light-induced structural adaptation remain to be addressed. In this study, we determine the crystal structure of the photosensory domain of Arabidopsis CRY2 in a tetrameric active state. Systematic structurebased analyses of photo-activated and inactive plant CRYs elucidate new structural elements and critical residues that dynamically partake in photo-induced oligomerization. Our study offers an updated model of CRYs photoactivation mechanism as well as the mode of its regulation by interacting proteins.
Filariasis causing nematode Brugia malayi is shown to harbor wolbachia bacteria as symbionts. The sequenced genome of the wolbachia endosymbiont from B.malayi (wBm) offers an unprecedented opportunity to identify new wolbachia drug targets. Genome analysis of the glycolytic/gluconeogenic pathway has revealed that wBm lacks pyruvate kinase (PK) and may instead utilize the enzyme pyruvate phosphate dikinase (PPDK; ATP: pyruvate, orthophosphate phosphotransferase, EC 2.7.9.1). PPDK catalyses the reversible conversion of AMP, PPi and phosphoenolpyruvate into ATP, Pi and pyruvate. Most organisms including mammals exclusively possess PK. Therefore the absence of PPDK in mammals makes this enzyme as attractive wolbachia drug target. In the present study we have modeled the three dimensional structure of wBm PPDK. The template with 50% identity and 67% similarity in amino acid sequence was employed for homology-modeling approach. The putative active site consists of His476, Arg360, Glu358, Asp344, Arg112, Lys43 and Glu346 was selected as site of interest for designing suitable inhibitor molecules. Docking studies were carried out using induced fit algorithms with OPLS force field of Schrödinger's Glide. The lead molecules which inhibit the PPDK activity are taken from the small molecule library (Pubchem database) and the interaction analysis showed that these compounds may inhibit the function of PPDK in wBm.
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