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"Hill, Chris"
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What does it mean to be global?
Teaches children about respecting other countries and cultures and what it means to be a community.
Book
The mechanism of glycosphingolipid degradation revealed by a GALC-SapA complex structure
Sphingolipids are essential components of cellular membranes and defects in their synthesis or degradation cause severe human diseases. The efficient degradation of sphingolipids in the lysosome requires lipid-binding saposin proteins and hydrolytic enzymes. The glycosphingolipid galactocerebroside is the primary lipid component of the myelin sheath and is degraded by the hydrolase β-galactocerebrosidase (GALC). This enzyme requires the saposin SapA for lipid processing and defects in either of these proteins causes a severe neurodegenerative disorder, Krabbe disease. Here we present the structure of a glycosphingolipid-processing complex, revealing how SapA and GALC form a heterotetramer with an open channel connecting the enzyme active site to the SapA hydrophobic cavity. This structure defines how a soluble hydrolase can cleave the polar glycosyl headgroups of these essential lipids from their hydrophobic ceramide tails. Furthermore, the molecular details of this interaction provide an illustration for how specificity of saposin binding to hydrolases is encoded.
Lysosomal degradation of sphingolipids requires lipid-binding saposin proteins and hydrolytic enzymes. Here the authors present the crystal structure of the hydrolase β-galactocerebrosidase in complex with saposin SapA and give insights into the glycosphingolipid galactocerebroside degradation mechanism.
Journal Article
Structure of the Fanconi anaemia monoubiquitin ligase complex
The Fanconi anaemia (FA) pathway repairs DNA damage caused by endogenous and chemotherapy-induced DNA crosslinks, and responds to replication stress
1
,
2
. Genetic inactivation of this pathway by mutation of genes encoding FA complementation group (FANC) proteins impairs development, prevents blood production and promotes cancer
1
,
3
. The key molecular step in the FA pathway is the monoubiquitination of a pseudosymmetric heterodimer of FANCD2–FANCI
4
,
5
by the FA core complex—a megadalton multiprotein E3 ubiquitin ligase
6
,
7
. Monoubiquitinated FANCD2 then recruits additional protein factors to remove the DNA crosslink or to stabilize the stalled replication fork. A molecular structure of the FA core complex would explain how it acts to maintain genome stability. Here we reconstituted an active, recombinant FA core complex, and used cryo-electron microscopy and mass spectrometry to determine its structure. The FA core complex comprises two central dimers of the FANCB and FA-associated protein of 100 kDa (FAAP100) subunits, flanked by two copies of the RING finger subunit, FANCL. These two heterotrimers act as a scaffold to assemble the remaining five subunits, resulting in an extended asymmetric structure. Destabilization of the scaffold would disrupt the entire complex, resulting in a non-functional FA pathway. Thus, the structure provides a mechanistic basis for the low numbers of patients with mutations in FANCB, FANCL and FAAP100. Despite a lack of sequence homology, FANCB and FAAP100 adopt similar structures. The two FANCL subunits are in different conformations at opposite ends of the complex, suggesting that each FANCL has a distinct role. This structural and functional asymmetry of dimeric RING finger domains may be a general feature of E3 ligases. The cryo-electron microscopy structure of the FA core complex provides a foundation for a detailed understanding of its E3 ubiquitin ligase activity and DNA interstrand crosslink repair.
The structure of the multiprotein Fanconi anaemia core complex, determined using cryo-electron microscopy and mass spectrometry, shows that the complex adopts an extended asymmetric structure and highlights the structural and functional asymmetry of the RING finger domains.
Journal Article
The golem's game!
Despite being a great Minecraft player, Morgan feels his leadership of the team slipping away as the next splinter of the Evoker King takes the form of a golem and challenges each member of the team to run a dangerous obstacle course. Normally they would work together, but this time they are each forced to face the challenge alone--with no second chances and a river of hot lava waiting for them if they fail!
CHILDBOOK
Insights from structural studies of the cardiovirus 2A protein
Cardioviruses are single-stranded RNA viruses of the family Picornaviridae. In addition to being the first example of internal ribosome entry site (IRES) utilization, cardioviruses also employ a series of alternative translation strategies, such as Stop-Go translation and programmed ribosome frameshifting. Here, we focus on cardiovirus 2A protein, which is not only a primary virulence factor, but also exerts crucial regulatory functions during translation, including activation of viral ribosome frameshifting and inhibition of host cap-dependent translation. Only recently, biochemical and structural studies have allowed us to close the gaps in our knowledge of how cardiovirus 2A is able to act in diverse translation-related processes as a novel RNA-binding protein. This review will summarize these findings, which ultimately may lead to the discovery of other RNA-mediated gene expression strategies across a broad range of RNA viruses.
Journal Article
ما معنى أن أكون عالميا ؟
مجموعة من المفاهيم البسيطة التي تساعد الطفل على أن يدرك كيف يكون عالميا من خلال أن لغته ليست سوى واحدة من بين آلاف اللغات وأن هناك اختلافات كبيرة بين الأفراد في بقاع الأرض كافة من حيث المأكولات والتقاليد والأديان، فعلينا أن نتقبل هذا الاختلاف وأن نكون منفتحين على العالم بأكمله فأن أكون عالميا يعني أن أكون مواطنا من العالم.
BOOK
Architecture of eukaryotic mRNA 3′-end processing machinery
Newly transcribed eukaryotic precursor messenger RNAs (pre-mRNAs) are processed at their 3′ ends by the ~1-megadalton multiprotein cleavage and polyadenylation factor (CPF). CPF cleaves pre-mRNAs, adds a polyadenylate tail, and triggers transcription termination, but it is unclear how its various enzymes are coordinated and assembled. Here, we show that the nuclease, polymerase, and phosphatase activities of yeast CPF are organized into three modules. Using electron cryomicroscopy, we determined a 3.5-angstrom-resolution structure of the ~200-kilodalton polymerase module. This revealed four β propellers, in an assembly markedly similar to those of other protein complexes that bind nucleic acid. Combined with in vitro reconstitution experiments, our data show that the polymerase module brings together factors required for specific and efficient polyadenylation, to help coordinate mRNA 3′-end processing.
Journal Article
Structurally heterogeneous ribosomes cooperate in protein synthesis in bacterial cells
Ribosome heterogeneity is a paradigm in biology, pertaining to the existence of structurally distinct populations of ribosomes within a single organism or cell. This concept suggests that structurally distinct pools of ribosomes have different functional properties and may be used to translate specific mRNAs. However, it is unknown to what extent structural heterogeneity reflects genuine functional specialization rather than stochastic variations in ribosome assembly. Here, we address this question by combining cryo-electron microscopy and tomography to observe individual structurally heterogeneous ribosomes in bacterial cells. We show that 70% of ribosomes in
Psychrobacter urativorans
contain a second copy of the ribosomal protein bS20 at a previously unknown binding site on the large ribosomal subunit. We then determine that this second bS20 copy appears to be functionally neutral. This demonstrates that ribosome heterogeneity does not necessarily lead to functional specialization, even when it involves significant variations such as the presence or absence of a ribosomal protein. Instead, we show that heterogeneous ribosomes can cooperate in general protein synthesis rather than specialize in translating discrete populations of mRNA.
Cells can simultaneously produce structurally dissimilar ribosomes, suggesting functional specialization of distinct ribosome populations. Here, the authors show that distinct ribosomes cooperate rather than specialize in protein synthesis.
Journal Article