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Shusuke Nambu Toshitaka Matsui Celia W. Goulding Satoshi Takahashi Masao Ikeda-Saito 《The Journal of biological chemistry》2013,288(14):10101-10109
MhuD is an oxygen-dependent heme-degrading enzyme from Mycobacterium tuberculosis with high sequence similarity (∼45%) to Staphylococcus aureus IsdG and IsdI. Spectroscopic and mutagenesis studies indicate that the catalytically active 1:1 heme-MhuD complex has an active site structure similar to those of IsdG and IsdI, including the nonplanarity (ruffling) of the heme group bound to the enzyme. Distinct from the canonical heme degradation, we have found that the MhuD catalysis does not generate CO. Product analyses by electrospray ionization-MS and NMR show that MhuD cleaves heme at the α-meso position but retains the meso-carbon atom at the cleavage site, which is removed by canonical heme oxygenases. The novel tetrapyrrole product of MhuD, termed “mycobilin,” has an aldehyde group at the cleavage site and a carbonyl group at either the β-meso or the δ-meso position. Consequently, MhuD catalysis does not involve verdoheme, the key intermediate of ring cleavage by canonical heme oxygenase enzymes. Ruffled heme is apparently responsible for the heme degradation mechanism unique to MhuD. In addition, MhuD heme degradation without CO liberation is biologically significant as one of the signals of M. tuberculosis transition to dormancy is mediated by the production of host CO. 相似文献
33.
Balázs Csaba Németh Thomas Wartmann Walter Halangk Miklós Sahin-Tóth 《The Journal of biological chemistry》2013,288(33):24049-24062
Chymotrypsin C (CTRC) is a proteolytic regulator of trypsinogen autoactivation in humans. CTRC cleavage of the trypsinogen activation peptide stimulates autoactivation, whereas cleavage of the calcium binding loop promotes trypsinogen degradation. Trypsinogen mutations that alter these regulatory cleavages lead to increased intrapancreatic trypsinogen activation and cause hereditary pancreatitis. The aim of this study was to characterize the regulation of autoactivation of mouse trypsinogens by mouse Ctrc. We found that the mouse pancreas expresses four trypsinogen isoforms to high levels, T7, T8, T9, and T20. Only the T7 activation peptide was cleaved by mouse Ctrc, causing negligible stimulation of autoactivation. Surprisingly, mouse Ctrc poorly cleaved the calcium binding loop in all mouse trypsinogens. In contrast, mouse Ctrc readily cleaved the Phe-150–Gly-151 peptide bond in the autolysis loop of T8 and T9 and inhibited autoactivation. Mouse chymotrypsin B also cleaved the same peptide bond but was 7-fold slower. T7 was less sensitive to chymotryptic regulation, which involved slow cleavage of the Leu-149–Ser-150 peptide bond in the autolysis loop. Modeling indicated steric proximity of the autolysis loop and the activation peptide in trypsinogen, suggesting the cleaved autolysis loop may directly interfere with activation. We conclude that autoactivation of mouse trypsinogens is under the control of mouse Ctrc with some notable differences from the human situation. Thus, cleavage of the trypsinogen activation peptide or the calcium binding loop by Ctrc is unimportant. Instead, inhibition of autoactivation via cleavage of the autolysis loop is the dominant mechanism that can mitigate intrapancreatic trypsinogen activation. 相似文献
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目的:丝裂原活化蛋白激酶(Mitogen-activated Protein Kinases, MAPKs)是细胞内重要的信号传导通路,双位点特异性磷酸酶(Mitogen-activated Protein Kinase Phosphatases, MKPs)去磷酸化MAPKs,负调控MAPKs的信号传递。在MKPs去磷酸化MAPKs的过程中,MAPKs同时会激活部分MKPs的催化能力,MKP1便是其中之一。本文旨在比较三种经典MAPKs底物,ERK2、JNK1和p38α对MKP1磷酸酶催化能力的激活效果,进一步理解MAPKs与MKP1的底物特异性机制。方法:以p NPP为底物,检测在不同浓度的非磷酸化ERK2、JNK1和p38α存在下,MKP1-CD催化结构域片段蛋白质去磷反应速度的变化,对比所得的动力学参数以确定MAPKs对MKP1激活程度的差异。结果:ERK2和JNK1能够激活MKP1的催化活力,将催化速率提升1.5~2倍,而ERK2与MKP1的结合力比JNK1弱约6倍;p38α则没有观察到对MKP1去磷酸化能力的激活效果。结论:三种经典MAPKs中,ERK2和JNK1能够激活MKP1催化活力,而p38α则无法激活MKP1,进一步揭示了MAPKs和MKPs间的特异性相互作用,以及底物对MKPs活力的影响。 相似文献
35.
《Molecular & cellular proteomics : MCP》2019,18(1):65-85
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- •Natural substrates of FAP were identified using degradomic and proteomic techniques and FAP gene knockout mouse derived embryonic fibroblasts stably transduced with enzymatically active or inactive FAP.
- •Terminal amine isotopic labelling of substrates (TAILS) based degradomics identified cleavage sites in collagens, and many other extracellular matrix (ECM) and associated proteins.
- •Cleavages of lysyl oxidase-like-1, CXCL-5, CSF-1 and C1qT6 by FAP were confirmed in vitro.
- •Differential metabolic labelling coupled with quantitative proteomic analysis implicated FAP in regulating proteins that are associated with ECM, ECM-cell interactions, coagulation, metabolism and wound healing.
36.
Amanda Rui En Woo Siu Kwan Sze Hwa Hwa Chung Valerie C-L Lin 《Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms》2019,1862(4):522-533
The activation functions AF1 and AF2 of nuclear receptors mediate the recruitment of coregulators in gene regulation. AF1 is mapped to the highly variable and intrinsically unstructured N terminal domain and AF2 lies in the conserved ligand binding domain. The unstructured nature of AF1 offers structural plasticity and hence functional versatility in gene regulation. However, little is known about the key functional residues of AF1 that mediates its interaction with coregulators. This study focuses on the progesterone receptor (PR) and reports the identification of K464, K481 and R492 (KKR) as the key functional residues of PR AF1. The KKR are monomethylated and function cooperatively. The combined mutations of KKR to QQQ render PR isoform B (PRB) hyperactive, whereas KKR to FFF mutations abolishes as much as 80% of PR activity. Furthermore, the hyperactive QQQ mutation rescues the loss of PR activity due to E911A mutation in AF2. The study also finds that the magnitudes of the mutational effect differ in different cell types as a result of differential effects on the functional interaction with coregulators. Furthermore, KKR provides the interface for AF1 to physically interact with p300 and SRC-1, and with AF2 at E911. Intriguingly, the inactive FFF mutant interacts strikingly stronger with both SRC-1 and AF2 than wt PRB. We propose a tripartite model to describe the dynamic interactions between AF1, AF2 and SRC-1 with KKR of AF1 and E911 of AF2 as the interface. An overly stable interaction would hamper the dynamics of disassembly of the receptor complex. 相似文献
37.
Interaction between single molecules of Mac-1 and ICAM-1 in living cells: an atomic force microscopy study 总被引:6,自引:1,他引:5
The interaction between integrin macrophage differentiation antigen associated with complement three receptor function (Mac-1) and intercellular adhesion molecule-1 (ICAM-1), which is controlled tightly by the ligand-binding activity of Mac-1, is central to the regulation of neutrophil adhesion in host defense. Several "inside-out" signals and extracellular metal ions or antibodies have been found to activate Mac-1, resulting in an increased adhesiveness of Mac-1 to its ligands. However, the molecular basis for Mac-1 activation is not well understood yet. In this work, we have carried out a single-molecule study of Mac-1/ICAM-1 interaction force in living cells by atomic force microscopy (AFM). Our results showed that the binding probability and adhesion force of Mac-1 with ICAM-1 increased upon Mac-1 activation. Moreover, by comparing the dynamic force spectra of different Mac-1 mutants, we expected that Mac-1 activation is governed by the downward movement of its alpha7 helix. 相似文献
38.
Given its tri-planar action at the hip, strengthening of gluteus maximus (GMAX) has been advocated as part of rehabilitation and injury prevention protocols for various musculoskeletal conditions. However, recruitment of GMAX during weight-bearing strengthening exercises can be challenging owing to the muscular redundancy at the hip for a given joint motion. The current study sought to determine if a 1-week activation program could result in greater GMAX recruitment during functional strengthening exercises. Pre- and post-training surface electromyography were collected from 12 healthy participants as they performed double- and single-leg squats. Between testing sessions, participants completed a GMAX activation training program consisting of isometric exercises with band resistance (twice per day for 7 days). Following the 1-week activation program, GMAX recruitment was found to increase by 57% during the double-leg squat (p = 0.005, Cohen’s r = 0.73) and 53% during the single-leg squat (p = 0.006, Cohen’s r = 0.70). Implementation of an initial GMAX activation program should be considered to facilitate neuromuscular adaptations that facilitate utilization of GMAX during hip strengthening exercises. 相似文献
39.
The role of the CcpA transcriptional regulator in carbon metabolism in Bacillus subtilis 总被引:2,自引:0,他引:2
Tina M. Henkin 《FEMS microbiology letters》1996,135(1):9-15
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