The proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically eliminated and which ...molecular characteristics direct them for removal are fundamental questions. We reveal a mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase uses interchangeable substrate receptors to recognize the unusual C termini of abnormal proteins (i.e., C-end degrons). C-end degrons are mostly less than ten residues in length and comprise a few indispensable residues along with some rather degenerate ones. The C-terminal end position is essential for C-end degron function. Truncated selenoproteins generated by translation errors and the USP1 N-terminal fragment from post-translational cleavage are eliminated by DesCEND. DesCEND also targets full-length proteins with naturally occurring C-end degrons. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” as indicators for protein elimination.
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•CRL2 ubiquitin ligase functions in protein quality control•CRL2 recognizes the unusual C-termini of aberrant proteins (i.e., C-end degrons)•CRL2 recognizes various C-end degrons through interchangeable substrate receptors•CRL2 also targets full-length proteins with naturally occurring C-end degrons
Lin et al. uncover a protein degradation mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase recognizes and eliminates proteins with exposed C-end degrons through interchangeable substrate receptors. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” in directing protein elimination.
Protein termini are determinants of protein stability. Proteins bearing degradation signals, or degrons, at their amino‐ or carboxyl‐termini are eliminated by the N‐ or C‐degron pathways, ...respectively. We aimed to elucidate the function of C‐degron pathways and to unveil how normal proteomes are exempt from C‐degron pathway‐mediated destruction. Our data reveal that C‐degron pathways remove mislocalized cellular proteins and cleavage products of deubiquitinating enzymes. Furthermore, the C‐degron and N‐degron pathways cooperate in protein removal. Proteome analysis revealed a shortfall in normal proteins targeted by C‐degron pathways, but not of defective proteins, suggesting proteolysis‐based immunity as a constraint for protein evolution/selection. Our work highlights the importance of protein termini for protein quality surveillance, and the relationship between the functional proteome and protein degradation pathways.
SYNOPSIS
Proteins with degradation signals (degron) at their amino‐ or carboxyl‐termini are eliminated by the N‐ or C‐degron pathways, respectively. Proteome‐wide analyses suggest functions of human C‐degrons signals in protein quality surveillance, as well as interplay with N‐degron‐dependent mechanisms.
The Global Protein Stability (GPS) random peptide platform enables context‐independent characterization of degron features.
The activity of C‐degrons is tuned by their surrounding sequences.
Gly/C‐degron shortage is limited to functional eukaryotic proteomes accessible to C‐degron pathways.
C‐degron pathways clear products of proteases and mislocalized cellular proteins.
Mitochondrial localization of MIC19 is dually safeguarded by the N‐ and C‐degron pathways.
Coronaviral diGly‐ending proteins evade C‐degron pathway‐mediated degradation.
Proteome‐wide analyses suggest functions of C‐terminal degradation signals in protein quality surveillance as well as interplay with N‐degron‐dependent mechanisms.
Selenocysteine (Sec) is translated from the codon UGA, typically a termination signal. Codon duality extends the genetic code; however, the coexistence of two competing UGA-decoding mechanisms ...immediately compromises proteome fidelity. Selenium availability tunes the reassignment of UGA to Sec. We report a CRL2 ubiquitin ligase–mediated protein quality-control system that specifically eliminates truncated proteins that result from reassignment failures. Exposing the peptide immediately N-terminal to Sec, a CRL2 recognition degron, promotes protein degradation. Sec incorporation destroys the degron, protecting read-through proteins from detection by CRL2. Our findings reveal a coupling between directed translation termination and proteolysis-assisted protein quality control, as well as a cellular strategy to cope with fluctuations in organismal selenium intake.
A novel Risley prism (RP) integrated with phase-correcting dielectric lens (PCDLs) is designed and demonstrated at V-band (50-75 GHz) for 2-D beam-steering performance with consistent high-gain ...attributes. The proposed design consists of a pair of dielectric wedges built using high permittivity material integrated with a parabolic PCDL built using a low permittivity material. The proposed RP integrated with PCDL exhibits wideband steering of the incident beam into a 3-D conical space via concurrent axial rotation of the RP elements. The proposed beam-steering structure is capable of providing a consistent gain of ~24 dBi at the V-band based on the aperture size of the RP and the PCDL. The wideband performance of the proposed RP design is experimentally demonstrated using a commercial 20 dBi pyramidal standard gain horn operating at V-band (50-75 GHz). The simulated and measured gain of the proposed arrangement with the pyramidal horn along the broadside are found to be 24.6 and 23.1 dBi, respectively at 62.5 GHz. The proposed work exhibits consistent gain with deviation less than 1.3 dB and scan losses below 2 dB for scan angles of ±40° throughout the V-band (50-75 GHz). The measurement results validate the wideband steering performance of the proposed mechanism. The effect of rotation errors on the steering performance of the proposed design is also investigated.
Understanding elementary excitations and their couplings in condensed matter systems is critical for developing better energy-conversion devices. In thermoelectric materials, the heat-to-electricity ...conversion efficiency is directly improved by suppressing the propagation of phonon quasiparticles responsible for macroscopic thermal transport. The current record material for thermoelectric conversion efficiency, SnSe, has an ultralow thermal conductivity, but the mechanism behind the strong phonon scattering remains largely unknown. From inelastic neutron scattering measurements and first-principles simulations, we mapped the four-dimensional phonon dispersion surfaces of SnSe, and found the origin of the ionic-potential anharmonicity responsible for the unique properties of SnSe. We show that the giant phonon scattering arises from an unstable electronic structure, with orbital interactions leading to a ferroelectric-like lattice instability. The present results provide a microscopic picture connecting electronic structure and phonon anharmonicity in SnSe, and offers new insights on how electron-phonon and phonon-phonon interactions may lead to the realization of ultralow thermal conductivity.
Abstract
AbstractThe T2-FLAIR (fluid attenuated inversion recovery) mismatch sign is an easily detectable imaging sign on routine clinical MRI studies that suggests diagnosis of isocitrate ...dehydrogenase (IDH)–mutant 1p/19q non-codeleted gliomas. Multiple independent studies show that the T2-FLAIR mismatch sign has near-perfect specificity, but low sensitivity for diagnosing IDH-mutant astrocytomas. Thus, the T2-FLAIR mismatch sign represents a non-invasive radiogenomic diagnostic finding with potential clinical impact. Recently, false positive cases have been reported, many related to variable application of the sign’s imaging criteria and differences in image acquisition, as well as to differences in the included patient populations. Here we summarize the imaging criteria for the T2-FLAIR mismatch sign, review similarities and differences between the multiple validation studies, outline strategies to optimize its clinical use, and discuss potential opportunities to refine imaging criteria in order to maximize its impact in glioma diagnostics.
Lower-grade gliomas (WHO grade II/III) have been classified into clinically relevant molecular subtypes based on
and 1p/19q mutation status. The purpose was to investigate whether T2/FLAIR MRI ...features could distinguish between lower-grade glioma molecular subtypes.
MRI scans from the TCGA/TCIA lower grade glioma database (
= 125) were evaluated by two independent neuroradiologists to assess (i) presence/absence of homogenous signal on T2WI; (ii) presence/absence of "T2-FLAIR mismatch" sign; (iii) sharp or indistinct lesion margins; and (iv) presence/absence of peritumoral edema. Metrics with moderate-substantial agreement underwent consensus review and were correlated with glioma molecular subtypes. Somatic mutation, DNA copy number, DNA methylation, gene expression, and protein array data from the TCGA lower-grade glioma database were analyzed for molecular-radiographic associations. A separate institutional cohort (
= 82) was analyzed to validate the T2-FLAIR mismatch sign.
Among TCGA/TCIA cases, interreader agreement was calculated for lesion homogeneity
= 0.234 (0.111-0.358), T2-FLAIR mismatch sign
= 0.728 (0.538-0.918), lesion margins
= 0.292 (0.135-0.449), and peritumoral edema
= 0.173 (0.096-0.250). All 15 cases that were positive for the T2-FLAIR mismatch sign were
-mutant, 1p/19q non-codeleted tumors (
< 0.0001; PPV = 100%, NPV = 54%). Analysis of the validation cohort demonstrated substantial interreader agreement for the T2-FLAIR mismatch sign
= 0.747 (0.536-0.958); all 10 cases positive for the T2-FLAIR mismatch sign were
-mutant, 1p/19q non-codeleted tumors (
< 0.00001; PPV = 100%, NPV = 76%).
Among lower-grade gliomas, T2-FLAIR mismatch sign represents a highly specific imaging biomarker for the
-mutant, 1p/19q non-codeleted molecular subtype.
.
Abstract
Protein complexes are the fundamental units of many biological functions. Despite their many advantages, one major adverse impact of protein complexes is accumulations of unassembled ...subunits that may disrupt other processes or exert cytotoxic effects. Synthesis of excess subunits can be inhibited via negative feedback control or they can be degraded more efficiently than assembled subunits, with this latter being termed cooperative stability. Whereas controlled synthesis of complex subunits has been investigated extensively, how cooperative stability acts in complex formation remains largely unexplored. To fill this knowledge gap, we have built quantitative models of heteromeric complexes with or without cooperative stability and compared their behaviours in the presence of synthesis rate variations. A system displaying cooperative stability is robust against synthesis rate variations as it retains high dimer/monomer ratios across a broad range of parameter configurations. Moreover, cooperative stability can alleviate the constraint of limited supply of a given subunit and makes complex abundance more responsive to unilateral upregulation of another subunit. We also conducted an in silico experiment to comprehensively characterize and compare four types of circuits that incorporate combinations of negative feedback control and cooperative stability in terms of eight systems characteristics pertaining to optimality, robustness and controllability. Intriguingly, though individual circuits prevailed for distinct characteristics, the system with cooperative stability alone achieved the most balanced performance across all characteristics. Our study provides theoretical justification for the contribution of cooperative stability to natural biological systems and represents a guideline for designing synthetic complex formation systems with desirable characteristics.
In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the ...promoters of more than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes -- the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.
Primary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking ...surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC-GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection.
To clarify the optimal timing of surgical therapy in advanced ovarian cancer.
Primary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer.
TRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB-IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB-IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations.
Major inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB-IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy.
Overall survival.
772 patients.
Accrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024.
NCT02828618.
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