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Analysis of proteome dynamics in the mouse brain
Advances in systems biology have allowed for global analyses of mRNA and protein expression, but large-scale studies of protein dynamics and turnover have not been conducted in vivo. Protein turnover is an important metabolic and regulatory mechanism in establishing proteome homeostasis, impacting many physiological and pathological processes. Here, we have used organism-wide isotopic labeling to measure the turnover rates of ∼2,500 proteins in multiple mouse tissues, spanning four orders of magnitude. Through comparison of the brain with the liver and blood, we show that within the respective tissues, proteins performing similar functions often have similar turnover rates. Proteins in the brain have significantly slower turnover (average lifetime of 9.0 d) compared with those of the liver (3.0 d) and blood (3.5 d). Within some organelles (such as mitochondria), proteins have a narrow range of lifetimes, suggesting a synchronized turnover mechanism. Protein subunits within complexes of variable composition have a wide range of lifetimes, whereas those within well-defined complexes turn over in a coordinated manner. Together, the data represent the most comprehensive in vivo analysis of mammalian proteome turnover to date. The developed methodology can be adapted to assess in vivo proteome homeostasis in any model organism that will tolerate a labeled diet and may be particularly useful in the analysis of neurodegenerative diseases in vivo.
Journal Article
Structure of the Cdc48 segregase in the act of unfolding an authentic substrate
The cellular machine Cdc48 functions in multiple biological pathways by segregating its protein substrates from a variety of stable environments such as organelles or multi-subunit complexes. Despite extensive studies, the mechanismof Cdc48 has remained obscure, and its reported structures are inconsistent with models of substrate translocation proposed for other AAA+ ATPases (adenosine triphosphatases). Here, we report a 3.7-angstrom–resolution structure of Cdc48 in complex with an adaptor protein and a native substrate. Cdc48 engages substrate by adopting a helical configuration of substrate-binding residues that extends through the central pore of both of the ATPase rings. These findings indicate a unified hand-over-hand mechanism of protein translocation by Cdc48 and other AAA+ ATPases.
Journal Article
Active conformation of the p97-p47 unfoldase complex
The p97 AAA+ATPase is an essential and abundant regulator of protein homeostasis that plays a central role in unfolding ubiquitylated substrates. Here we report two cryo-EM structures of human p97 in complex with its p47 adaptor. One of the conformations is six-fold symmetric, corresponds to previously reported structures of p97, and lacks bound substrate. The other structure adopts a helical conformation, displays substrate running in an extended conformation through the pore of the p97 hexamer, and resembles structures reported for other AAA unfoldases. These findings support the model that p97 utilizes a “hand-over-hand” mechanism in which two residues of the substrate are translocated for hydrolysis of two ATPs, one in each of the two p97 AAA ATPase rings. Proteomics analysis supports the model that one p97 complex can bind multiple substrate adaptors or binding partners, and can process substrates with multiple types of ubiquitin modification.
The p97 unfoldase is an essential and abundant enzyme that segregates its substrates from macromolecular complexes and organelle membranes. Here, authors determined the structure of human p97 in the act of unfolding an authentic substrate.
Journal Article
The Cyril Scott companion : unity in diversity
This Companion explores the life and work of this remarkably creative man. It provides a comprehensive analysis and appraisal of all the available music and includes a complete catalogue of his musical works, along with a discography. Several works...both music and literary are here newly catalogued and discussed. Altogether, the volume gives a broad picture of Scott's entire output in literary, dramatic and philosophical genres.--Publisher
Book
Quality of Life in Post-Surgical Hypoparathyroidism (PoSH) in Thyroid and Parathyroid Surgery
Background
Post-surgical hypoparathyroidism (PoSH) is often long term, with significant associated morbidity and ongoing treatment. A recent systematic review found impaired quality of life (QoL) in patients with PoSH, despite stable treatment. Most studies did not include an appropriate control arm and further studies were recommended, taking into account underlying disease and comorbidities. This study aims to compare QoL in patients with PoSH with appropriate control groups.
Methods
This was a cross-sectional observational study using the general quality of life SF-36 tool and a hypocalcaemia symptom score (HcSS) to assess QoL in patients with PoSH and controls (who had similar surgery but without PoSH). Participants were identified from two patient groups (the Butterfly Thyroid Cancer Trust and the Association for Multiple Endocrine Neoplasia Disorders) and a single tertiary centre in the UK.
Results
Four hundred and thirty-nine responses (female
n
= 379, PoSH
n
= 89) were included with a median (range) age of 52 (19–92) years. Reported dates of surgery ranged from 1973 to 2019. HcSS scores showed significantly more associated symptoms in patients with PoSH than those without (
p
< 0.001). Although there was no overall difference in QoL between groups, patients with PoSH consistently had lower scores (
p
= 0.008) in the energy/fatigue subdomain of the SF-36.
Conclusion
Patients with PoSH reported significantly more fatigue and loss of energy compared to appropriately matched controls, but overall QoL was not significantly different. Standardised QoL measures may not be sensitive enough to highlight the impact on QoL in these patients. A disease-specific tool may be required.
Journal Article
Identifying indirect selection traits to improve winter hardiness in barley
A lack of reliable winter hardiness has impeded the adoption of winter barley (Hordeum vulgare L.) in much of the northern United States. Direct selection for winter survival is time consuming and often unreliable. In addition, because survival is a binary trait, selection towards small quantitative gains can be difficult. One solution to these challenges is to identify indirect selection traits: anatomical or physiological characteristics which can be measured in the absence of winter stress, but which contribute to improved winter survival. Here, we survey a range of winter and spring barley, as well as winter wheat, winter rye, and perennial species of the genus Hordeum, all of which are more winter hardy than barley, to identify traits associated with winter survival. We identified several traits as promising candidates for selection. These included crown depth and leaf metaxylem diameter, which previous studies have identified as indirect selection traits. New candidates identified by our study include crown diameter and leaf midvein and blade thickness, as well as a suite of traits which suggest a pattern of reduced and efficient investment in above-ground structures. The effect of these traits on winter survival need to be validated and quantified by further experiments, but they represent a promising early step in a potentially valuable breeding strategy.
Journal Article
Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway
The Cdc48 AAA+ ATPase is an abundant and essential enzyme that unfolds substrates in multiple protein quality control pathways. The enzyme includes two conserved AAA+ ATPase motor domains, D1 and D2, that assemble as hexameric rings with D1 stacked above D2. Here, we report an ensemble of native structures of Cdc48 affinity purified from budding yeast lysate in complex with the adaptor Shp1 in the act of unfolding substrate. Our analysis reveals a continuum of structural snapshots that spans the entire translocation cycle. These data uncover elements of Shp1-Cdc48 interactions and support a ‘hand-over-hand’ mechanism in which the sequential movement of individual subunits is closely coordinated. D1 hydrolyzes ATP and disengages from substrate prior to D2, while D2 rebinds ATP and re-engages with substrate prior to D1, thereby explaining the dominant role played by the D2 motor in substrate translocation/unfolding.
The Cdc48 enzyme is an abundant and essential enzyme that functions in many cellular pathways as a protein unfoldase. Here, the authors determine an ensemble of Cdc48 structures that capture snapshots of its unfolding action using a ‘hand-over-hand’ mechanism.
Journal Article