Spare-part management in a heterogeneous environment.
Ontology highlight
ABSTRACT:
SUBMITTER: Barabadi R
PROVIDER: S-EPMC7978368 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pyruvate formate-lyase (PFL) is a glycyl radical enzyme (GRE) that converts pyruvate and coenzyme A into acetyl-CoA and formate in a reaction that is crucial to the primary metabolism of many anaerobic bacteria. The glycyl radical cofactor, which is posttranslationally installed by a radical S-adenosyl-L-methionine (SAM) activase, is a simple and effective catalyst, but is also susceptible to oxidative damage in microaerobic environments. Such damage occurs at the glycyl radical cofactor, resulting in cleaved PFL (cPFL). Bacteria have evolved a spare part protein termed YfiD that can be used to repair cPFL. Previously, we obtained a structure of YfiD by NMR spectroscopy and found that the N-terminus of YfiD was disordered and that the C-terminus of YfiD duplicates the structure of the C-terminus of PFL, including a β-strand that is not removed by the oxygen-induced cleavage. We also showed that cPFL is highly susceptible to proteolysis, suggesting that YfiD rescue of cPFL competes with protein degradation. Here, we probe the mechanism by which YfiD can bind and restore activity to cPFL through enzymatic and spectroscopic studies. Our data show that the disordered N-terminal region of YfiD is important for YfiD glycyl radical installation but not for catalysis, and that the duplicate β-strand does not need to be cleaved from cPFL for YfiD to bind. In fact, truncation of this PFL region prevents YfiD rescue. Collectively our data suggest the molecular mechanisms by which YfiD activation is precluded both when PFL is not damaged and when it is highly damaged.
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Project description:We investigate the probability of fixation of a new mutation arising in a metapopulation that ranges over a heterogeneous selective environment. Using simulations, we test the performance of several approximations of this probability, including a new analytical approximation based on separation of the timescales of selection and migration. We extend all approximations to multideme metapopulations with arbitrary population structure. Our simulations show that no single approximation produces accurate predictions of fixation probabilities for all cases of potential interest. At the limits of low and high migration, previously published approximations are found to be highly accurate. The new separation-of-timescales approach provides the best approximations for intermediate rates of migration among habitats, provided selection is not too intense. For nonzero migration and relatively strong selection, all approximations perform poorly. However, the probability of fixation is bounded above and below by the approximations based on low and high migration limits. Surprisingly, in our simulations with symmetric migration, heterogeneous selection in a metapopulation never decreased-and sometimes substantially increased-the probability of fixation of a new allele compared to metapopulations experiencing homogeneous selection with the same mean selection intensity.
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Project description:Glycyl radical enzymes (GREs) utilize a glycyl radical cofactor to carry out a diverse array of chemically challenging enzymatic reactions in anaerobic bacteria. Although the glycyl radical is a powerful catalyst, it is also oxygen sensitive such that oxygen exposure causes cleavage of the GRE at the site of the radical. This oxygen sensitivity presents a challenge to facultative anaerobes dwelling in areas prone to oxygen exposure. Once GREs are irreversibly oxygen damaged, cells either need to make new GREs or somehow repair the damaged one. One particular GRE, pyruvate formate lyase (PFL), can be repaired through the binding of a 14.3 kDa protein, termed YfiD, which is constitutively expressed in E. coli. Herein, we have solved a solution structure of this 'spare part' protein using nuclear magnetic resonance spectroscopy. These data, coupled with data from circular dichroism, indicate that YfiD has an inherently flexible N-terminal region (residues 1-60) that is followed by a C-terminal region (residues 72-127) that has high similarity to the glycyl radical domain of PFL. Reconstitution of PFL activity requires that YfiD binds within the core of the PFL barrel fold; however, modeling suggests that oxygen-damaged, i.e. cleaved, PFL cannot fully accommodate YfiD. We further report that a PFL variant that mimics the oxygen-damaged enzyme is highly susceptible to proteolysis, yielding additionally truncated forms of PFL. One such PFL variant of ~?77 kDa makes an ideal scaffold for the accommodation of YfiD. A molecular model for the rescue of PFL activity by YfiD is presented.
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Project description:ObjectiveAlveolar soft part sarcomas (ASPS) which has high potential ability of metastasis, is a rare and slowly growing malignant tumor, and mainly primary localized in limbs. To date, little is known about the best treatment of ASPS. This study aims to review the current management and advance of ASPS.MethodsWANFANG MED ONLINE, CNKI, and NCBI PUBMED were used to search literature spanning from 1963 to 2020, and all cases of ASPS about "ASPS, diagnosis, treatment, surgery, radiotherapy, chemotherapy, target therapy or immune therapy" with detailed data were included.ResultsComplete surgical resection remained the standard management strategy, radiotherapy was reported to be used for the patients of micro- or macroscopical incomplete residue or the surgical margin was questionable. Chemotherapy was controversial. Some target drugs and immune checkpoint inhibitors had produced antitumor activity.ConclusionComplete surgical resection is the cure treatment for ASPS, and adjuvant chemotherapy is not recommended excepted clinical trials. For the patients with micro- or macroscopical incomplete residue, radiotherapy should be appreciated. Furthermore, for recurrence, distant metastasis, and refractory of ASPS, combination therapy, especially combination with multiple target agents and/or immune checkpoint inhibitors may prolong survival time.
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