Shaolian Zhou

Bio: Shaolian Zhou is an academic researcher from Novartis. The author has contributed to research in topics: Electrospray ionization & Histone methyltransferase. The author has an hindex of 21, co-authored 32 publications receiving 2155 citations. Previous affiliations of Shaolian Zhou include University of Tennessee & Hoffmann-La Roche.

An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED

Abstract: Polycomb repressive complex 2 (PRC2) consists of three core subunits, EZH2, EED and SUZ12, and plays pivotal roles in transcriptional regulation. The catalytic subunit EZH2 methylates histone H3 lysine 27 (H3K27), and its activity is further enhanced by the binding of EED to trimethylated H3K27 (H3K27me3). Small-molecule inhibitors that compete with the cofactor S-adenosylmethionine (SAM) have been reported. Here we report the discovery of EED226, a potent and selective PRC2 inhibitor that directly binds to the H3K27me3 binding pocket of EED. EED226 induces a conformational change upon binding EED, leading to loss of PRC2 activity. EED226 shows similar activity to SAM-competitive inhibitors in blocking H3K27 methylation of PRC2 target genes and inducing regression of human lymphoma xenograft tumors. Interestingly, EED226 also effectively inhibits PRC2 containing a mutant EZH2 protein resistant to SAM-competitive inhibitors. Together, we show that EED226 inhibits PRC2 activity via an allosteric mechanism and offers an opportunity for treatment of PRC2-dependent cancers.

Abeta amyloid fibrils possess a core structure highly resistant to hydrogen exchange.

Abstract: We describe here experiments designed to characterize the secondary structure of amyloid fibrils of the Alzheimer's amyloid plaque peptide Abeta, using hydrogen-deuterium exchange measurements evaluated by mass spectrometry. The results show that approximately 50% of the amide protons of the polypeptide backbone of Abeta(1-40) resist exchange in aqueous, neutral pH buffer even after more than 1, 000 h of incubation at room temperature. We attribute this extensive, strong protection to H-bonding by residues in core regions of beta-sheet structure within the fibril. The backbone amide hydrogens exchange at variable rates, suggesting different degrees of protection within the fibril. These data suggest that it is unlikely that the entire Abeta sequence is involved in H-bonded secondary structure within the amyloid fibril. Future studies using the methods described here should reveal further details of Abeta fibril structure and assembly. These methods also should be amenable to studies of other amyloid fibrils and protein aggregates.

Post-Transcriptional Modification in Archaeal tRNAs: Identities and Phylogenetic Relations of Nucleotides from Mesophilic and Hyperthermophilic Methanococcales

Abstract: Post-transcriptional modifications in archaeal RNA are known to be phylogenetically distinct but relatively little is known of tRNA from the Methanococci, a lineage of methanogenic marine euryarchaea that grow over an unusually broad temperature range. Transfer RNAs from Methanococcus vannielii, Methanococcus maripaludis, the thermophile Methanococcus thermolithotrophicus, and hyperthermophiles Methanococcus jannaschii and Methanococcus igneus were studied to determine whether modification patterns reflect the close phylogenetic relationships inferred from small ribosomal subunit RNA sequences, and to examine modification differences associated with temperature of growth. Twenty-four modified nucleosides were characterized, including the complex tricyclic nucleoside wyosine characteristic of position 37 in tRNA(Phe) and known previously only in eukarya, plus two new wye family members of presently unknown structure. The hypermodified nucleoside 5-methylaminomethyl-2-thiouridine, reported previously only in bacterial tRNA at the first position of the anticodon, was identified by liquid chromatography-electrospray ionization mass spectrometry in four of the five organisms. The ribose-methylated nucleosides, 2'-O-methyladenosine, N(2),2'-O-dimethylguanosine and N(2),N(2),2'-O-trimethylguanosine, were found only in hyperthermophile tRNA, consistent with their proposed roles in thermal stabilization of tRNA.

Protein Misfolding, Functional Amyloid, and Human Disease

Abstract: Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.

Atomic structures of amyloid cross-beta spines reveal varied steric zippers.

Abstract: Amyloid fibrils formed from different proteins, each associated with a particular disease, contain a common cross-β spine. The atomic architecture of a spine, from the fibril-forming segment GNNQQNY of the yeast prion protein Sup35, was recently revealed by X-ray microcrystallography. It is a pair of β-sheets, with the facing side chains of the two sheets interdigitated in a dry ‘steric zipper’. Here we report some 30 other segments from fibril-forming proteins that form amyloid-like fibrils, microcrystals, or usually both. These include segments from the Alzheimer’s amyloid-β and tau proteins, the PrP prion protein, insulin, islet amyloid polypeptide (IAPP), lysozyme, myoglobin, α-synuclein and β2-microglobulin, suggesting that common structural features are shared by amyloid diseases at the molecular level. Structures of 13 of these microcrystals all reveal steric zippers, but with variations that expand the range of atomic architectures for amyloid-like fibrils and offer an atomic-level hypothesis for the basis of prion strains. Degenerative diseases such as Alzheimer's and Parkinson's are associated with the precipitation of amyloid fibrils in the brain. The fibrils are remarkably uniform in structure, considering the diversity of the proteins that produce them. Sawaya et al. have now identified 30 short fibril-forming peptides taken from a large range of amyloid diseases and have solved the atomic structures of crystals formed by 13 of them. All the peptides so far examined self-assemble by forming variants of the 'steric zipper', a structural feature first found in the yeast prion protein Sup 35. The zipper may be a key to the strength of amyloid fibrils, and is a prime target for therapeutic intervention. Degenerative diseases such as Alzheimer's or Parkinson's are associated with the misfolding of many diverse proteins, yet the amyloid fibrils formed by all these proteins are similar. David Eisenberg and colleagues have now identified 30 short fibril-forming peptides implicated in a range of amyloid diseases and have solved 13 of their atomic structures, revealing variations in one common feature — the 'steric zipper'.

3D structure of Alzheimer's amyloid-β(1–42) fibrils

Abstract: Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.