Febs Letters

doi: 10.1016/S0014-5793(15)00169-6pmid: N/A

Hatzihristidis, Teri; Desai, Nikita; Hutchins, Andrew P.; Meng, Tzu-Ching; Tremblay, Michel L.; Miranda-Saavedra, Diego

doi: 10.1016/j.febslet.2015.03.005pmid: 25771859

Most of our knowledge on protein tyrosine phosphatases (PTPs) is derived from human pathologies and mouse knockout models. These models largely correlate well with human disease phenotypes, but can be ambiguous due to compensatory mechanisms introduced by paralogous genes. Here we present the analysis of the PTP complement of the fruit fly and the complementary view that PTP studies in Drosophila will accelerate our understanding of PTPs in physiological and pathological conditions. With only 44 PTP genes, Drosophila represents a streamlined version of the human complement. Our integrated analysis places the Drosophila PTPs into evolutionary and functional contexts, thereby providing a platform for the exploitation of the fly for PTP research and the transfer of knowledge onto other model systems.

Fernández, Ariel

doi: 10.1016/j.febslet.2015.03.002pmid: 25771861

This work explores the participation of protein packing defects, the so‐called dehydrons, in biochemical events. We delineate the enabling role of dehydrons as activators of nucleophilic groups. This activation results from the induction of chemical basicity in interfacial water molecules, promoting deprotonation of adjacent nucleophiles. Through multiple steering molecular dynamics with pulling along the proton‐displacement coordinate, we show that nucleophilic groups are functionally enabled by nearby dehydrons that promote proton transference. The computations are validated against experimentally determined pKa decreases at functional sites and biochemical probes of deregulated catalytic activity arising from dehydron‐generating mutations.

Akıncılar, Semih Can; Low, Kee Chung; Liu, Chia Yi; Yan, Ting Dong; Oji, Asami; Ikawa, Masahito; Li, Shang; Tergaonkar, Vinay

doi: 10.1016/j.febslet.2015.02.035pmid: 25749370

Besides its canonical function of catalyzing the formation of telomeric repeats, many groups have recently reported non‐canonical functions of hTERT in particular, and telomerase in general. Regulating transcription is the central basis of non‐canonical functions of telomerase. However, unlike reverse transcriptase activity of telomerase that requires only a few molecules of enzymatically active hTERT, non‐canonical functions of hTERT or other telomerase components theoretically require several hundred copies. Here, we provide the first direct quantification of all the telomerase components in human cancer cell lines. We demonstrate that telomerase components do not exist in a 1:1 stoichiometric ratio, and there are several hundred copies of hTERT in cells. This provides the molecular basis of hTERT to function in other signaling cascades, including transcription.

Caron, Danielle; Boutchueng-Djidjou, Martial; Tanguay, Robert M.; Faure, Robert L.

doi: 10.1016/j.febslet.2015.03.007pmid: 25775977

Insulin receptor (IR) endocytosis requires a remodelling of the actin cytoskeleton. We show here that ANXA2 is SUMOylated at the K10 located in a non‐consensus SUMOylation motif in the N‐terminal domain. The Y24F mutation decreased the SUMOylation signal, whereas insulin stimulation increased ANXA2 SUMOylation. A survey of protein SUMOylation in hepatic Golgi/endosome (G/E) fractions after insulin injections revealed the presence of a SUMOylation pattern and confirmed the SUMOylation of ANXA2. The construction of an IR/ANXA2/SUMO network (IRASGEN) in the G/E context reveals the presence of interacting nodes whereby SUMO1 connects ANXA2 to actin and microtubule‐mediated changes in membrane topology. Heritable variants associated with type 2 diabetes represent 41% of the IRASGEN thus pointing out the physio‐pathological importance of this subnetwork.

Contet, Alicia; Pihan, Emilie; Lavigne, Marina; Wengelnik, Kai; Maheshwari, Sweta; Vial, Henri; Douguet, Dominique; Cerdan, Rachel

doi: 10.1016/j.febslet.2015.03.003pmid: 25771858

Phosphatidylcholine is the major lipid component of the malaria parasite membranes and is required for parasite multiplication in human erythrocytes. Plasmodium falciparum CTP:phosphocholine cytidylyltransferase (PfCCT) is the rate‐limiting enzyme of the phosphatidylcholine biosynthesis pathway and thus considered as a potential antimalarial target. In contrast to its mammalian orthologs, PfCCT contains a duplicated catalytic domain. Here, we show that both domains are catalytically active with similar kinetic parameters. A virtual screening strategy allowed the identification of a drug‐size molecule competitively inhibiting the enzyme. This compound also prevented phosphatidylcholine biosynthesis in parasites and exerted an antimalarial effect. This study constitutes the first step towards a rationalized design of future new antimalarial agents targeting PfCCT.

Duggan, Stephen P.; Yan, Run; McCarthy, Justin V.

doi: 10.1016/j.febslet.2015.03.008pmid: 25796185

The presenilins (PS1 and PS2) are the catalytic component of the γ‐secretase intramembrane protease complex, involved in the regulated intramembrane proteolysis of numerous type I transmembrane proteins, including amyloid precursor protein (APP) and Notch. Herein, we describe the identification and characterization of a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin‐binding domain (UBD) in PS1, and demonstrate that the CUE domain of PS1 mediates non‐covalent binding to Lysine 63‐linked polyubiquitin chains. Our results highlight a γ‐secretase‐independent function for non‐covalent ubiquitin signaling in the regulation of PS1, and add new insights into the structure and function of the presenilin proteins.

Oh, Mi-Kyung; Park, Hyo-Jung; Lee, Joo-Hyun; Bae, Hyun-Mi; Kim, In-Sook

doi: 10.1016/j.febslet.2015.03.006pmid: 25775978

Prohaptoglobin (proHp) is processed into mature haptoglobin via site‐specific cleavage. Although haptoglobin has been well studied, the functions of proHp remain unclear. We investigated the angiogenic action of proHp in endothelial cells, demonstrating that proHp upregulated vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression and endothelial sprouting and branching. ProHp‐induced sprouting was attenuated by a VEGFR2 inhibitor. Moreover, proHp was detected in sera of cancer patients by immunoprecipitation and Western blot. These findings indicate that proHp promotes angiogenesis via VEGF/VEGFR2 signalling, and serum proHp level may be a useful biomarker for diseases associated with angiogenesis.

Li, Ming; Zhou, Wei; Yuan, Rongfa; Chen, Leifeng; Liu, Tiande; Huang, Da; Hao, Liang; Xie, Yuancai; Shao, Jianghua

doi: 10.1016/j.febslet.2015.03.004pmid: 25771860

Rho‐associated kinase 2 (Rock2) is known to promote tumorigenesis in hepatocellular carcinoma (HCC). CCAAT/enhancer‐binding protein delta (CEBPD) functions as a tumor suppressor. In this study, we found that the expression of Rock2 and CEBPD are inversely correlated. Knockdown of Rock2 increased CEBPD expression and inhibited the proliferation of HCC cells in vitro and in vivo. Mechanistically, we found that Rock2 regulates CEBPD expression through the p‐GSK3β/β‐catenin pathway. Taken together, we identified a novel Rock2–p‐GSK3β/β‐catenin–CEBPD regulatory circuitry, the dysfunction of which may contribute to the tumorigenic characteristic of HCC.

Wicker-Planquart, Catherine; Jault, Jean-Michel

doi: 10.1016/j.febslet.2015.03.001pmid: 25771857

The stoichiometry of YsxC ribosome subunit complex was evaluated. We showed that YsxC binding to the 50S ribosomal subunit is not affected by GTP, but in the presence of GDP the stoichiometry of YsxC‐ribosome is decreased. YsxC GTPase activity was stimulated upon 50S ribosomal subunit binding. In addition, it is shown for the first time that YsxC binds both 16S and 23S ribosomal RNAs.