Protein folding and surface interaction phase diagrams in vitro and in cells
AbstractProtein stability is subject to environmental perturbations such as pressure and crowding, as well as sticking to other macromolecules and quinary structure. Thus, the environment inside and outside the cell plays a key role in how proteins fold, interact and function on the scale from a few molecules to macroscopic ensembles. This review discusses three aspects of protein phase diagrams. First, the relevance of phase diagrams to protein folding and functionin vitro and in cells. Next, how the evolution of protein surfaces impacts on interaction phase diagrams. And finally, how phase separation plays a role on much...
Source: FEBS Letters - February 12, 2021 Category: Biochemistry Authors: Martin Gruebele Tags: IN A NUTSHELL Source Type: research

Strain ‐Level Immunomodulatory Variation of Gut Bacteria
AbstractThe gut microbiota and the immune system have co ‐evolved to interact and cooperate in many ways. A recent study characterizing the immunomodulatory effects of over 60 different human‐derived gut microbes across phyla showed that bacteria‐induced immunomodulations are not dictated by the bacterial phylogeny. Yet, it remains unclear whether s trains from the same species induce the same immunomodulatory effects on the host. We analyzed the strain‐level data from this recent study and found that strains from the same species can induce distinct and sometimes even opposing immunophenotypes. Hence, we suggest t...
Source: FEBS Letters - February 11, 2021 Category: Biochemistry Authors: Haitham Hajjo, Naama Geva ‐Zatorsky Tags: RESEARCH LETTER Source Type: research

Corrigendum
(Source: FEBS Letters)
Source: FEBS Letters - February 8, 2021 Category: Biochemistry Tags: Corrigendum Source Type: research

Front Cover
Cover illustration The cover image is taken from the article “Experimentally based structural model of Yih1 provides insight into its function in controlling the key translational regulator Gcn2” by E. Harjes et al. (pp. 324–340). (Source: FEBS Letters)
Source: FEBS Letters - February 8, 2021 Category: Biochemistry Tags: Issue Information Source Type: research

Bridging the gap between scientists and citizens: basic research can be accessible for all
(Source: FEBS Letters)
Source: FEBS Letters - February 7, 2021 Category: Biochemistry Authors: Daniela Ruffell Tags: The Scientists ’ Forum Source Type: research

Does the ATP ‐bound EQ mutant reflect the pre‐ or post‐ATP hydrolysis state in the catalytic cycle of human P‐glycoprotein (ABCB1)?
AbstractP ‐glycoprotein (P‐gp, ABCB1) is an ABC transporter associated with the development of multidrug resistance to chemotherapy. During its catalytic cycle, P‐gp undergoes significant conformational changes. Recently, atomic structures of some of these conformations have been resolved using cryo‐e lectron microscopy. The ATP hydrolysis‐defective mutant of the catalytic glutamate residue of the Walker B motif (E556Q/E1201Q) has been used to determine the structure of the ATP‐bound inward‐closed conformation of P‐gp. Here we show that this mutant does not appear to undergo the same step s as wild‐type P...
Source: FEBS Letters - February 6, 2021 Category: Biochemistry Authors: Sabrina Lusvarghi, Stewart R. Durell, Suresh V. Ambudkar Tags: RESEARCH LETTER Source Type: research

Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species ‐specific conformations
AbstractAn assembly of multi ‐protein complexes achieves chromosomal DNA replication at the replication fork. In eukaryotes, proliferating cell nuclear antigen (PCNA) plays a vital role in the assembly of multi‐protein complexes at the replication fork and is essential for cell viability. PCNA from several organisms, includ ingSaccharomyces cerevisiae, have been structurally characterised. However, the structural analyses of PCNA from fungal pathogens are limited. Recently, we have reported that PCNA from the opportunistic fungal pathogenCandida albicans complements the essential functions of ScPCNA inS. cerevisiae. St...
Source: FEBS Letters - February 5, 2021 Category: Biochemistry Authors: Rajivgandhi Sundaram, Kodavati Manohar, Shraddheya Kumar Patel, Narottam Acharya, Dileep Vasudevan Tags: RESEARCH ARTICLE Source Type: research

Crystal structure of l ‐rhamnose 1‐dehydrogenase involved in the nonphosphorylative pathway of l‐rhamnose metabolism in bacteria
Several microorganisms can utilizel‐rhamnose as a carbon and energy source through the nonphosphorylative metabolic pathway, in whichl‐rhamnose 1‐dehydrogenase (RhaDH) catalyzes the NAD(P)+‐dependent oxidization ofl‐rhamnose tol‐rhamnono‐1,4‐lactone. We herein investigated the crystal structures of RhaDH fromAzotobacter  vinelandii in ligand ‐free, NAD+‐bound, NADP+‐bound, andl‐rhamnose‐ and NAD+‐bound forms at 1.9, 2.1, 2.4, and 1.6 Å resolution, respectively. The significant interactions with the 2′‐phosphate group of NADP+, but not the 2 ′‐hydroxyl group of NAD...
Source: FEBS Letters - February 5, 2021 Category: Biochemistry Authors: Kentaroh Yoshiwara, Seiya Watanabe, Yasunori Watanabe Tags: Research Letter Source Type: research

PTEN is required for the migration and invasion of Ras ‐transformed MDCK cells
AbstractThe balance between phosphoinositides distributed at specific sites in the plasma membrane causes polarized actin polymerization. Oncogenic transformations affect this balance by regulating phosphoinositide 3 ‐kinase (PI3K) and phosphatase and tensin homolog deleted on chromosome ten (PTEN), causing metastatic behavior in cancer cells. Here, we show that the PTEN tumor suppressor gene is required for epithelial cancer cell invasion. Loss of PTEN in Ras‐transformed MDCK cells suppressed their migrator y phenotype in collagen gel and invasion through Matrigel. Rescue experiments showed a requirement for the C2 do...
Source: FEBS Letters - February 4, 2021 Category: Biochemistry Authors: Lu Yan, Kazuya Tsujita, Yasuyuki Fujita, Toshiki Itoh Tags: RESEARCH ARTICLES Source Type: research

Pleiotrophin Interacts with Glycosaminoglycans in a Highly Flexible and Adaptable Manner
We examined the specificity of PTN for several types of GAG oligosaccharides. Our data indicate that the interaction of PTN with GAGs is dependent on the sulfation density of GAGs. Surprisingly, an acidic peptide also had similar interactions with PTN as GAGs. This shows that the interaction of PTN with anionic polymers is flexible and adaptable and that the charge density is the main determinant of the interaction. In addition, we show that PTN can compensate for the loss of its termini in interactions with heparin oligosaccharides, allowing it to maintain its affinity for GAGs in the absence of the termini. Taken togethe...
Source: FEBS Letters - February 2, 2021 Category: Biochemistry Authors: Eathen Ryan, Di Shen, Xu Wang Tags: RESEARCH ARTICLES Source Type: research

The bridge helix of Cas12a imparts selectivity in cis ‐DNA cleavage and regulates trans‐DNA cleavage
AbstractCas12a is an RNA ‐guided DNA endonuclease of the type V‐A CRISPR‐Cas system that has evolved convergently with the type II Cas9 protein. We previously showed that proline substitutions in the bridge helix (BH) impart target DNA cleavage selectivity inStreptococcus pyogenes (Spy) Cas9. Here, we examined a BH variant of Cas12a fromFrancisella novicida (FnoCas12aKD2P) to test mechanistic conservation. Our results show that for RNA ‐guided DNA cleavage (cis ‐activity), FnoCas12aKD2P accumulates nicked products while cleaving supercoiled DNA substrates with mismatches, with certain mismatch positions being mor...
Source: FEBS Letters - February 1, 2021 Category: Biochemistry Authors: Hari Priya Parameshwaran, Kesavan Babu, Christine Tran, Kevin Guan, Aleique Allen, Venkatesan Kathiresan, Peter Z. Qin, Rakhi Rajan Tags: RESEARCH ARTICLES Source Type: research

Human Fibroblast ‐derived Extracellular Vesicles Promote Hair Growth in Cultured Human Hair Follicles
In this study, we investigate the effects of a specific class of extracellular vesicles (EVs), namely human normal fibroblast ‐derived EVs (hFB‐EVs), on human dermal papilla (DP) and outer root sheath (ORS) cells and examine the molecular mechanisms responsible for hair growth in hair follicles (HFs). We find that Wnt3a, which maintains the hair‐generating activity of DP cells, is enriched and more strongly associate d with hFB‐EVs than with fibroblasts. Furthermore, hFB‐EV‐associated Wnt3a mediated receptor activation in cultured DP cells, leading to an increase in β‐catenin in the cytoplasm and its tra...
Source: FEBS Letters - February 1, 2021 Category: Biochemistry Authors: Ramya Lakshmi Rajendran, Prakash Gangadaran, Mi Hee Kwack, Ji Min Oh, Chae Moon Hong, Young Kwan Sung, Jaetae Lee, Byeong ‐Cheol Ahn Tags: RESEARCH ARTICLES Source Type: research

The molecular pathology of pathogenic mitochondrial tRNA variants
AbstractMitochondrial diseases are clinically and genetically heterogeneous disorders, caused by pathogenic variants in either the nuclear or mitochondrial genome. This heterogeneity is particularly striking for disease caused by variants in mitochondrial DNA ‐encoded tRNA (mt‐tRNA) genes, posing challenges for both the treatment of patients and for understanding the molecular pathology. In this review, we consider disease caused by the two most common pathogenic mt‐tRNA variants: m.3243A>G (withinMT ‐TL1, encoding mt ‐tRNALeu(UUR)) and m.8344A>G (withinMT ‐TK, encoding mt ‐tRNALys), which together acco...
Source: FEBS Letters - January 29, 2021 Category: Biochemistry Authors: Uwe Richter, Robert McFarland, Robert W Taylor, Sarah J Pickett Tags: REVIEW Source Type: research

Subunits of the GPI transamidase complex localize to the endoplasmic reticulum and nuclear envelope in Drosophila
AbstractA total of 10 –20% of plasma membrane proteins are anchored by glycosylphosphatidylinositol (GPI). GPI is attached to proteins by GPI transamidase (GPI‐T), which contains five subunits named PIGK, PIGS, PIGT, PIGU, and GPAA1. We previously reported that PIGT localizes near the nucleus inDrosophila. However, localizations of the other four subunits remain unknown. Here, we show that a catalytic subunit of GPI ‐T, PIGK, mainly localizes to the endoplasmic reticulum (ER), while the other four subunits localize to the nuclear envelope (NE) and ER. The NE/ER localization ratio of PIGS differs between cell type...
Source: FEBS Letters - January 28, 2021 Category: Biochemistry Authors: Kohei Kawaguchi, Miki Yamamoto ‐Hino, Nina Matsuyama, Emiko Suzuki, Satoshi Goto Tags: RESEARCH LETTER Source Type: research

Front Cover
Cover illustration The cover image is taken from the article “The high‐resolution X‐ray structure of vinca‐domain inhibitors of microtubules provides a rational approach for drug design” by W. Chengyong et al. (pp. 195–205). (Source: FEBS Letters)
Source: FEBS Letters - January 25, 2021 Category: Biochemistry Tags: Issue Information Source Type: research

Galectin ‐1–RNA interaction map reveals potential regulatory roles in angiogenesis
This study applied the iRIP‐seq methodology to study the potential role of galectin‐1 as an RNA‐binding protein. We found that galectin‐1 interacts with a large number of mRNAs, with a preference for binding near stop codons and a preference for UGCA/UGGA and GAGCAG as binding motifs. Galectin‐1 binds to the mRNAs of angiogenesis‐associated genes includingVEGFA,EGR1 andLAMA5, suggesting that galectin ‐1 may regulate angiogenesis via its mRNA‐binding activity. We further show that shLGALS1 inhibits capillary tube formation in anin vitro angiogenesis assay and alters the expression levels of several galectin ...
Source: FEBS Letters - January 23, 2021 Category: Biochemistry Authors: Jiajun Wei, Daniel K. Li, Xinyu Hu, Chao Cheng, Yi Zhang Tags: RESEARCH ARTICLE Source Type: research

Crystal structure of L ‐rhamnose 1‐dehydrogenase involved in the non‐phosphorylative pathway of L‐rhamnose metabolism in bacteria
AbstractSeveral microorganisms can utilize L ‐rhamnose as a carbon and energy source through the non‐phosphorylative metabolic pathway, in which L‐rhamnose 1‐dehydrogenase (RhaDH) catalyzes the NAD(P)+‐dependent oxidization of L‐rhamnose to L‐rhamnono‐1,4‐lactone. We herein investigated the crystal structures of RhaDH fromAzotobacter vinelandii in ligand ‐free, NAD+‐bound, NADP+‐bound, and L‐rhamnose‐ and NAD+‐bound forms at 1.9, 2.1, 2.4, and 1.6 Å resolution, respectively. The significant interactions with the 2’‐phosphate group of NADP+, but not the 2 ’‐hydroxyl group ...
Source: FEBS Letters - January 22, 2021 Category: Biochemistry Authors: Kentaroh Yoshiwara, Seiya Watanabe, Yasunori Watanabe Tags: RESEARCH LETTER Source Type: research

Galectin ‐1–RNA interaction map reveals potential regulatory roles in angiogenesis
This study applied the iRIP‐seq methodology to study the potential role of galectin‐1 as an RNA‐binding protein. We found that galectin‐1 interacts with a large number of mRNAs, with a preference for binding near stop codons and a preference for UGCA/UGGA and GAGCAG as binding motifs. Galectin‐1 binds to the mRNAs of angiogenesis‐associated genes includingVEGFA,EGR1 andLAMA5, suggesting that galectin ‐1 may regulate angiogenesis via its mRNA‐binding activity. We further show that shLGALS1 inhibits capillary tube formation in anin vitro angiogenesis assay and alters the expression levels of several galectin ...
Source: FEBS Letters - January 22, 2021 Category: Biochemistry Authors: Jiajun Wei, Daniel K. Li, Xinyu Hu, Chao Cheng, Yi Zhang Tags: RESEARCH ARTICLE Source Type: research

Coding triplets in the tRNA acceptor ‐TΨC arm and their role in present and past tRNA recognition
AbstractThe mechanism and evolution of the recognition scheme between key components of the translation system, i.e., tRNAs, synthetases and elongation factors, are fundamental issues in understanding the translation of genetic information into proteins. Statistical analysis of bacterial tRNA sequences reveals that for six amino acids, a string of 10 nucleotides preceding the tRNA 3 ’end, carries cognate coding triplets to nearly full extent. The triplets conserved in positions 63‐67 are implicated in the recognition by the elongation factor EF‐Tu, and those conserved in positions 68‐72, in the identification o...
Source: FEBS Letters - January 18, 2021 Category: Biochemistry Authors: Ilana Agmon, Itay Fayerverker, Tal Mor Tags: RESEARCH ARTICLES Source Type: research

Adhesion ‐dependent Caveolin‐1 Tyrosine‐14 phosphorylation is regulated by FAK in response to changing matrix stiffness
Integrin ‐mediated adhesion regulates cellular responses to changes in the mechanical and biochemical properties of the extracellular matrix. Cell–matrix adhesion regulates caveolar endocytosis, dependent on caveolin 1 (Cav1) Tyr14 phosphorylation (pY14Cav1), to control anchorage‐dependent signaling. W e find that cell–matrix adhesion regulates pY14Cav1 levels in mouse fibroblasts. Biochemical fractionation reveals endogenous pY14Cav1 to be present in caveolae and focal adhesions (FA). Adhesion does not affect caveolar pY14Cav1, supporting its regulation at FA, in which PF‐228‐mediated inhib ition of fo...
Source: FEBS Letters - January 18, 2021 Category: Biochemistry Authors: Natasha Buwa, Nivedhika Kannan, Shaunak Kanade, Nagaraj Balasubramanian Tags: Research Letter Source Type: research

Coding triplets in the tRNA acceptor ‐TΨC arm and their role in present and past tRNA recognition
AbstractThe mechanism and evolution of the recognition scheme between key components of the translation system, i.e., tRNAs, synthetases and elongation factors, are fundamental issues in understanding the translation of genetic information into proteins. Statistical analysis of bacterial tRNA sequences reveals that for six amino acids, a string of 10 nucleotides preceding the tRNA 3 ’end, carries cognate coding triplets to nearly full extent. The triplets conserved in positions 63‐67 are implicated in the recognition by the elongation factor EF‐Tu, and those conserved in positions 68‐72, in the identification o...
Source: FEBS Letters - January 18, 2021 Category: Biochemistry Authors: Ilana Agmon, Itay Fayerverker, Tal Mor Tags: RESEARCH ARTICLES Source Type: research

Adhesion ‐dependent Caveolin‐1 Tyrosine‐14 phosphorylation is regulated by FAK in response to changing matrix stiffness
Integrin ‐mediated adhesion regulates cellular responses to changes in the mechanical and biochemical properties of the extracellular matrix. Cell–matrix adhesion regulates caveolar endocytosis, dependent on caveolin 1 (Cav1) Tyr14 phosphorylation (pY14Cav1), to control anchorage‐dependent signaling. W e find that cell–matrix adhesion regulates pY14Cav1 levels in mouse fibroblasts. Biochemical fractionation reveals endogenous pY14Cav1 to be present in caveolae and focal adhesions (FA). Adhesion does not affect caveolar pY14Cav1, supporting its regulation at FA, in which PF‐228‐mediated inhib ition of fo...
Source: FEBS Letters - January 17, 2021 Category: Biochemistry Authors: Natasha Buwa, Nivedhika Kannan, Shaunak Kanade, Nagaraj Balasubramanian Tags: Research Letter Source Type: research

15 ‐Deoxy‐Δ12,14‐prostaglandin J2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H‐Ras transformed human breast epithelial cells
AbstractSTAT3 has been considered as a potential target for development of anti ‐cancer therapeutics. Here, we report a novel mechanism by which the cyclopentenone prostaglandin,15‐deoxy‐Δ12,14‐prostaglandin J2 (15d ‐PGJ2) functions as an allosteric inhibitor of STAT3. 15d ‐PGJ2 inhibits phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3 in H ‐Ras‐transformed human mammary epithelial cells (MCF10A‐Ras) through the Michael addition reaction at cysteine 259 of STAT3. Comparative studies with 15d ‐PGJ2 analogues reveal that both C12 ‐C13 and C9‐C10 double ...
Source: FEBS Letters - January 16, 2021 Category: Biochemistry Authors: Su ‐Jung Kim, Nam‐Chul Cho, Bitnara Han, Kyeojin Kim, Young‐Il Hahn, Kwang Pyo Kim, Young Ger Suh, Bu‐Young Choi, Hye‐Kyung Na, Young‐Joon Surh Tags: RESEARCH ARTICLES Source Type: research

Mitochondrial proteases in human diseases
AbstractMitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins....
Source: FEBS Letters - January 16, 2021 Category: Biochemistry Authors: Maria Gomez ‐Fabra Gala, F.‐Nora Vögtle Tags: REVIEW Source Type: research

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways
AbstractThe lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain ‐containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co‐precipitates with, and is directly phosphorylated b y, mTOR. Using a phospho‐specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2‐media...
Source: FEBS Letters - January 16, 2021 Category: Biochemistry Authors: Andrea Gubas, Christina Karantanou, Doris Popovic, Georg Tascher, Marina E. Hoffmann, Anna Platzek, Nina Dawe, Ivan Dikic, Daniela S. Krause, David.G McEwan Tags: RESEARCH LETTER Source Type: research

Mitochondrial proteases in human diseases
AbstractMitochondria contain more than 1000 different proteins, including several proteolytic enzymes. These mitochondrial proteases form a complex system that performs limited and terminal proteolysis to build the mitochondrial proteome, maintain and control its functions or degrade mitochondrial proteins and peptides. During protein biogenesis presequence proteases cleave and degrade mitochondrial targeting signals to obtain mature functional proteins. Processing by proteases also exerts a regulatory role in modulation of mitochondrial functions and quality control enzymes degrade misfolded, aged or superfluous proteins....
Source: FEBS Letters - January 16, 2021 Category: Biochemistry Authors: Maria Gomez ‐Fabra Gala, F.‐Nora Vögtle Tags: REVIEW Source Type: research

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways
AbstractThe lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain ‐containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 co‐precipitates with, and is directly phosphorylated b y, mTOR. Using a phospho‐specific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2‐media...
Source: FEBS Letters - January 16, 2021 Category: Biochemistry Authors: Andrea Gubas, Christina Karantanou, Doris Popovic, Georg Tascher, Marina E. Hoffmann, Anna Platzek, Nina Dawe, Ivan Dikic, Daniela S. Krause, David.G McEwan Tags: RESEARCH LETTER Source Type: research

15 ‐Deoxy‐Δ12,14‐prostaglandin J2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H‐Ras transformed human breast epithelial cells
AbstractSTAT3 has been considered as a potential target for development of anti ‐cancer therapeutics. Here, we report a novel mechanism by which the cyclopentenone prostaglandin,15‐deoxy‐Δ12,14‐prostaglandin J2 (15d ‐PGJ2) functions as an allosteric inhibitor of STAT3. 15d ‐PGJ2 inhibits phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3 in H ‐Ras‐transformed human mammary epithelial cells (MCF10A‐Ras) through the Michael addition reaction at cysteine 259 of STAT3. Comparative studies with 15d ‐PGJ2 analogues reveal that both C12 ‐C13 and C9‐C10 double ...
Source: FEBS Letters - January 16, 2021 Category: Biochemistry Authors: Su ‐Jung Kim, Nam‐Chul Cho, Bitnara Han, Kyeojin Kim, Young‐Il Hahn, Kwang Pyo Kim, Young Ger Suh, Bu‐Young Choi, Hye‐Kyung Na, Young‐Joon Surh Tags: RESEARCH ARTICLES Source Type: research

Dynamics and electrostatics define an allosteric druggable site within the receptor ‐binding domain of SARS‐CoV2 spike protein
AbstractThe pathogenesis of the SARS ‐CoV2 virus initiates through recognition of the angiotensin‐converting enzyme 2 (ACE2) receptor of the host cells by the receptor‐binding domain (RBD) located at the spikes of the virus. Here, using molecular dynamics (MD) simulations, we have demonstrated the allosteric crosstalk within the RBD in the apo‐ and the ACE2 receptor‐bound states, revealing the contribution of the dynamics‐based correlated motions and the electrostatic energy perturbations to this crosstalk. While allostery, based on correlated motions, dominates inherent distal communication in the apo‐RBD, t...
Source: FEBS Letters - January 15, 2021 Category: Biochemistry Authors: Sayan Bhattacharjee, Rajanya Bhattacharyya, Jayati Sengupta Tags: RESEARCH ARTICLES Source Type: research

Front Cover
Cover illustration Structurally inherent self ‐regulation of AID. The top bottleneck represents substrate selection wherein the vast majority of AID complexes with ssDNA or DNA/RNA are catalytically non‐productive and the minor proportion of substrates that fit into the ssDNA or RNA binding grooves are recognized by a plastic combination of two or three of the 5 substrate binding grooves. The second bottleneck is that even after the formation of the rare AID:substrate complexes that position a dC proximal to the catalytic pocket, AID’s catalytic pocket has a higher probability of being closed, a phenomenon termed...
Source: FEBS Letters - January 11, 2021 Category: Biochemistry Tags: Issue Information Source Type: research

The high ‐resolution X‐ray structure of vinca‐domain inhibitors of microtubules provides a rational approach for drug design
In this study, we determined the high‐resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high‐resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca‐ domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt‐bridge and H‐bond interactions with Asp179β1 and Asn329α2. Our studies provided the structural basis for d...
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Wu Chengyong, Xian Jinghong, Wang Yanyan, Xiao Qing ‐Jie, Ma Lingling, Li Yuyan, Chen Hai, Lei Qian, Zhang Quan, Sun Bo, Wang Yuxi Tags: Research Article Source Type: research

Elf4 regulates lysosomal biogenesis and the mTOR pathway to promote clearance of Staphylococcus aureus in macrophages
AbstractStaphylococcus aureus (S. aureus) is a major cause of infectious disease. Macrophages can directly destroy most of the invading bacteria through the phagolysosomal pathway. E74 ‐like factor 4 (Elf4) is one of the important transcription factors that controls diverse pathogens, but the role of Elf4 in macrophage‐mediatedS. aureus eradication is unknown. Our data show that Elf4 is induced byS. aureus in macrophages. Elevated expression of Elf4 results in decreased bacterial load and inflammatory responses duringS. aureus infectionin vivo andin vitro. Elf4 ‐overexpressed macrophages have decreased mTOR activity ...
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Yanhua Kang, Tingyue Wu, Yan He, Yunfan He, Dongjiu Zhao Tags: RESEARCH ARTICLES Source Type: research

Fanconi anemia and mTOR pathways functionally interact during stalled replication fork recovery
In this study, we demonstrate that during replication stress mTOR interacts and cooperates with FANCD2 to provide cellular stability, mediate stalled replication fork restart and prevent nucleolytic degradation of the nascent DNA strands. Taken together, t his study unravels a novel functional cross‐talk between two important mechanisms: mTOR and FA DNA repair pathways that ensure genomic stability. (Source: FEBS Letters)
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Matthew Nolan, Kenneth Knudson, Marina K. Holz, Indrajit Chaudhury Tags: RESEARCH ARTICLES Source Type: research

Ring assembly of c subunits of F0F1 ‐ATP synthase in Propionigenium modestum requires YidC and UncI following MPIase‐dependent membrane insertion
AbstractThe c subunits of F0F1‐ATP synthase (F0c) assemble into a ring structure, following membrane insertion that is dependent on both glycolipid MPIase and protein YidC. We analyzed the insertion and assembly processes ofPropionigenium modestum F0c (Pm ‐F0c), of which the ring structure is resistant to SDS. Ring assembly of Pm ‐F0c requiresP. modestum UncI (Pm ‐UncI). Ring assembly ofin vitro synthesized Pm ‐F0c was observed when both YidC and Pm ‐UncI were reconstituted into liposomes ofE. coli phospholipids. Under the physiological conditions where spontaneous insertion had been blocked by diacylglycerol, ...
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Hanako Nishikawa, Kotoka Kanno, Yuta Endo, Ken ‐ichi Nishiyama Tags: RESEARCH LETTER Source Type: research

The high ‐resolution X‐ray structure of vinca‐domain inhibitors of microtubules provides a rational approach for drug design
In this study, we determined the high‐resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high‐resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca‐ domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt‐bridge and H‐bond interactions with Asp179β1 and Asn329α2. Our studies provided the structural basis for d...
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Wu Chengyong, Xian Jinghong, Wang Yanyan, Xiao Qing ‐Jie, Ma Lingling, Li Yuyan, Chen Hai, Lei Qian, Zhang Quan, Sun Bo, Wang Yuxi Tags: Research Article Source Type: research

Elf4 regulates lysosomal biogenesis and the mTOR pathway to promote clearance of Staphylococcus aureus in macrophages
AbstractStaphylococcus aureus (S. aureus) is a major cause of infectious disease. Macrophages can directly destroy most of the invading bacteria through the phagolysosomal pathway. E74 ‐like factor 4 (Elf4) is one of the important transcription factors that controls diverse pathogens, but the role of Elf4 in macrophage‐mediatedS. aureus eradication is unknown. Our data show that Elf4 is induced byS. aureus in macrophages. Elevated expression of Elf4 results in decreased bacterial load and inflammatory responses duringS. aureus infectionin vivo andin vitro. Elf4 ‐overexpressed macrophages have decreased mTOR activity ...
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Yanhua Kang, Tingyue Wu, Yan He, Yunfan He, Dongjiu Zhao Tags: RESEARCH ARTICLES Source Type: research

Fanconi anemia and mTOR pathways functionally interact during stalled replication fork recovery
In this study, we demonstrate that during replication stress mTOR interacts and cooperates with FANCD2 to provide cellular stability, mediate stalled replication fork restart and prevent nucleolytic degradation of the nascent DNA strands. Taken together, t his study unravels a novel functional cross‐talk between two important mechanisms: mTOR and FA DNA repair pathways that ensure genomic stability. (Source: FEBS Letters)
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Matthew Nolan, Kenneth Knudson, Marina K. Holz, Indrajit Chaudhury Tags: RESEARCH ARTICLES Source Type: research

Ring assembly of c subunits of F0F1 ‐ATP synthase in Propionigenium modestum requires YidC and UncI following MPIase‐dependent membrane insertion
AbstractThe c subunits of F0F1‐ATP synthase (F0c) assemble into a ring structure, following membrane insertion that is dependent on both glycolipid MPIase and protein YidC. We analyzed the insertion and assembly processes ofPropionigenium modestum F0c (Pm ‐F0c), of which the ring structure is resistant to SDS. Ring assembly of Pm ‐F0c requiresP. modestum UncI (Pm ‐UncI). Ring assembly ofin vitro synthesized Pm ‐F0c was observed when both YidC and Pm ‐UncI were reconstituted into liposomes ofE. coli phospholipids. Under the physiological conditions where spontaneous insertion had been blocked by diacylglycerol, ...
Source: FEBS Letters - January 10, 2021 Category: Biochemistry Authors: Hanako Nishikawa, Kotoka Kanno, Yuta Endo, Ken ‐ichi Nishiyama Tags: RESEARCH LETTER Source Type: research

AP ‐1 and NF‐κB synergize to transcriptionally activate latent HIV upon T‐cell receptor activation
In this study, we determined the contribution of the transcription factors NF‐κB, NFAT, and AP‐1 in the reactivation of latent HI V following T‐cell receptor (TCR) activation using Jurkat T‐cell clones harboring single latent HIV proviruses. Our findings demonstrate that during reactivation from latency, NF‐κB enhances HIV transcription while NFAT inhibits it by competing with NF‐κB for overlapping binding sites on t he HIV long terminal repeat (LTR). We have also demonstrated for the first time the molecular contribution of AP‐1 in the reactivation of HIV from latency, whereby AP‐1 synerg...
Source: FEBS Letters - January 9, 2021 Category: Biochemistry Authors: Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Mudit Tyagi Tags: RESEARCH ARTICLES Source Type: research

Identification of chemical compounds regulating PD ‐L1 by introducing HiBiT‐tagged cells
AbstractProgrammed death ‐ligand 1 (PD‐L1) is a co‐inhibitory molecule expressed on tumor cells. Immune checkpoint inhibitors focusing on the PD‐L1 mechanism are now being studied for the treatment of various cancer types. However, the regulatory mechanism of PD‐L1 is yet to be fully clarified, and a high‐throug hput system for comparing the abilities of small compounds in regulating PD‐L1 has not yet been established. Therefore, we created a HiBiT‐tagged lung adenocarcinoma cell line, PC9‐KI, for easier and faster detection of changes in PD‐L1 protein expression. Using PC9‐KI cells, we screened 1 ,28...
Source: FEBS Letters - January 9, 2021 Category: Biochemistry Authors: Yutaro Uchida, Takahide Matsushima, Ryota Kurimoto, Tomoki Chiba, Yuki Inutani, Hiroshi Asahara Tags: RESEARCH ARTICLE Source Type: research

NRG/ErbB signaling regulates neonatal muscle growth but not neuromuscular contractures in neonatal brachial plexus injury
AbstractNeonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that are driven by impaired growth of denervated muscles. A rare form of NBPI, which maintains afferent muscle innervation despite motor denervation, does not cause contractures. As afferent innervation regulates various aspects of skeletal muscle homeostasis through NRG/ErbB signaling, our current study investigated the role of this pathway in modulating contracture development. Through pharmacologic modification with an ErbB antagonist and NRG1 isoforms, we discovered that NRG/ErbB signaling does not modulate the development...
Source: FEBS Letters - January 9, 2021 Category: Biochemistry Authors: Brendan L Ho, Qingnian Goh, Sia Nikolaou, Liangjun Hu, Kritton Shay ‐Winkler, Roger Cornwall Tags: RESEARCH LETTER Source Type: research