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Mechanisms of MAGUK-mediated cellular junctional complex organization

第一作者:Ye, F

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2018; 48 (无)

Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are enriched in cellular junctions and essential for tissue development and homeostasis. Mutations of MAGUKs are linked to many human diseases including cancers, psychiatric disorders, and intellectual disabilities. MAGUKs share a common PDZ-SH3-GK tandem domain organization at the C-terminal end. In this review, we summarize the mechanistic basis governing target recognition and regulations of this binding by the PDZ-SH3-GK tandem of various MAGUKs. We also discuss recent discoveries showing unique folding features of MAGUK PDZ-SH3-GK tandems that facilitate ligand-induced oligomerization of MAGUKs and phase transition of MAGUK-assembled synaptic signaling complexes.

IF:7.05

Molecular mechanisms of RNA polymerase II transcription elongation elucidated by kinetic network models

第一作者:Unarta, IC

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2018; 49 (无)

Transcription elongation cycle (TEC) of RNA polymerase II (Pol II) is a process of adding a nucleoside triphosphate to the growing messenger RNA chain. Due to the long timescale events in Pol II TEC, an advanced computational technique, such as Markov State Model (MSM), is needed to provide atomistic mechanism and reaction rates. The combination of MSM and experimental results can be used to build a kinetic network model (KNM) of the whole TEC. This review provides a brief protocol to build MSM and KNM of the whole TEC, along with the latest findings of MSM and other computational studies of Pol II TEC. Lastly, we offer a perspective on potentially using a sequence dependent KNM to predict genome-wide transcription error.

IF:7.05

Peptide recognition, signaling and modulation of class B G protein-coupled receptors

第一作者:Cao, C

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2018; 51 (无)

Class B G protein-coupled receptors (GPCRs) are important drug targets in many human diseases, including type 2 diabetes, obesity, cardiovascular disease and neurodegeneration. Peptide hormones bind to these receptors through interactions with both the extracellular domain and transmembrane domain. Despite remarkable advances in structural studies of GPCRs, structural characterization of the full-length class B receptors remains extremely challenging due to their conformational complexity. The recently solved structures of class B GPCRs reveal the structural basis of peptide ligand recognition and modulation mechanisms of small molecule allosteric modulators. Furthermore, these structures provide essential insights into molecular mechanisms of class B GPCR signal transduction and modulation.

IF:7.05

Design of artificial enzymes by supramolecular strategies

第一作者:Wang, TT

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2018; 51 (无)

Enzymes are biomacromolecules with three-dimensional structures composed of peptide polymers via supramolecular interactions. Owing to the incredible catalytic efficiency and unique substrate selectivity, enzymes arouse considerable attention. To rival natural enzymes, various artificial enzymes have been developed over the last decades. Since supramolecular interactions play important roles in both substrate recognition and the process of enzymatic catalysis, designing artificial enzymes using supramolecular strategies is undoubtedly significant. Here we discuss the recent advances in constructing artificial enzymes using supramolecular platforms.

IF:7.05

Beyond histone acetylation-writing and erasing histone acylations

第一作者:Zhao, S

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2018; 53 (无)

Histone post-translational modifications are crucial epigenetic mechanisms regulating a variety of biological events. Besides histone lysine acetylation, a repertoire of acylation types have been identified, including formylation, propionylation, butyrylation, crotonylation, 2-hydroxyisobutyrylation, beta-hydroxybutyrylation, succinylation, malonylation, glutarylation and benzoylation. From a structural perspective, here we summarize the writers and erasers of histone acylations and explain the molecular basis of these enzymes catalyzing non-acetyl histone acylations with a focus on histone crotonylation and beta-hydroxybutyrylation. Histone acylation readout, non-histone acylations and metabolic regulation are also discussed in this review.

IF:7.05

Structural insights into ligand recognition and activation of plant receptor kinases

第一作者:Song, W

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017; 43 (无)

The large family of membrane-localized receptor kinases (RKs) has important roles in many aspects of plant physiology. RKs function to perceive external signals, leading to RK activation and downstream signaling. Progress has been recently made in structural elucidation of the mechanisms underlying ligand recognition and activation of RKs. These structural studies mainly on leucine-rich repeat RKs (LRR-RKs) support the idea that ligand-induced dimerization is an essential step for RK activation, though the modes for dimerization vary. Here we review the structural knowledge with an emphasis on the ligand recognition and activation mechanisms that are likely conserved in a subfamily of LRR-RKs.

IF:7.18

Structural characterization of mammalian bHLH-PAS transcription factors

第一作者:Wu, DL

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017; 43 (无)

The mammalian basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factors share common architectural features that include a bHLH DNA-binding domain and tandemly positioned PAS domains. The sixteen members of this family include the hypoxia-inducible factors (HIF-1 alpha and HIF-2 alpha), ARNT (also known as HIF-1 beta), CLOCK and BMAL1. Most bHLH-PAS proteins have been genetically linked to variety of diseases in humans, including cancers, metabolic syndromes and psychiatric conditions. To function as transcription factors, the bHLH-PAS proteins must form heterodimeric complexes. Recent crystallographic studies of HIF-alpha-ARNT and CLOCK-BMAL1 complexes have unveiled the organization of their multi-domain bHLH-PAS-A-PAS-B segments, revealing how these architectures can give rise to unique patterns of heterodimerization. As our structural understanding becomes better integrated with ligand-discovery and target gene identification, a more comprehensive picture of their architectural and functional properties will emerge.

IF:7.18

Computational design of ligand-binding proteins

第一作者:Yang, W

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017; 45 (无)

Custom-designed ligand-binding proteins with novel functions hold the potential for numerous applications. In recent years, the developments of computational methods together with high-throughput experimental screening techniques have led to the generation of novel, high-affinity ligand-binding proteins for given ligands. In addition, naturally occurring ligand-binding proteins have been computationally designed to recognize new ligands while keeping their original biological functions at the same time. Furthermore, metalloproteins have been successfully designed for novel functions and applications. Though much has been learned in these successful design cases, advances in our understanding of protein dynamics and functions related to ligand binding and development of novel computational strategies are necessary to further increase the success rate of computational protein-ligand binding design.

IF:7.18

Spectator no more, the role of the membrane in regulating ion channel function

第一作者:Pliotas, C

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017; 45 (无)

A pressure gradient across a curved lipid bilayer leads to a lateral force within the bilayer. Following ground breaking work on eukaryotic ion channels, it is now known that many proteins sense this change in the lateral tension and alter their functions in response. It has been proposed that responding to pressure differentials may be one of the oldest signaling mechanisms in biology. The most well characterized mechanosensing ion channels are the bacterial ones which open when the pressure differential hits a threshold. Recent studies on one of these channels, MscS, have developed a simple molecular model for how they sense and adapt to pressure. Biochemical and structural studies on mechanosensitive channels from eukaryotes have disclosed pressure sensing mechanisms. In this review, we highlight these findings and discuss the potential for a general model for pressure sensing.

IF:7.18

Readers, writers and erasers of N-6-methylated adenosine modification

第一作者:Wu, BX

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017; 47 (无)

N-6-methyladenosine (m6A) as the most prevalent internal modification in mammalian RNAs has been increasingly realized as an important reversible mark that participates in various biological processes and cancer pathogenesis. In this review, we discuss the catalytic mechanisms of MT-A70 domain family proteins for mediating adenosine N-6-methylation, the removal of this RNA mark by members of ALKB homologue domain family proteins, and the recognition of these m(6)A-modified RNAs by YTH domain family proteins. Our discussions focus on the recent advances in our understandings of the structural and functional properties of N-6-methyladenosine methyltransferases, demethylases and reader proteins. Overall, we aim to mechanistically explain the reversible and dynamic nature of this unique RNA internal modification that contributes to the complexity of RNA mediated gene regulation, and inspire new studies in epitranscriptomics.

IF:7.18

Cryo-EM structures of human gamma-secretase

第一作者:Yang, GH

期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY, 2017; 46 (无)

gamma-secretase, a membrane-embedded aspartate protease, catalyzes peptide bond hydrolysis of a large variety of type I integral membrane proteins exemplified by amyloid precursor protein (APP). Cleavage of APP leads to formation of beta-amyloid plaque, which is a hallmark of Alzheimer's disease (AD). Over 200 AD-associated mutations are mapped to presenilin 1 (PS1), the catalytic component of gamma-secretase. In the past three years, several cryo-electron microscopy (cryo-EM) structures of human gamma-secretase have been determined at near atomic resolutions. Here we summarize the methods involved and discuss structural features of gamma-secretase and the associated functional insights.

IF:7.18

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