Mutant Proteins

Publication Title: 
Molecular Aspects of Medicine

SIRT1 is the mammalian homologue of yeast silent information regulator (Sir)-2, a member of the sirtuin family of protein deacetylases which have gained much attention as mediators of lifespan extension in several model organisms. Induction of SIRT1 expression also attenuates neuronal degeneration and death in animal models of Alzheimer's disease and Huntington's disease. SIRT1 induction, either by sirtuin activators such as resveratrol, or metabolic conditioning associated with caloric restriction (CR), could be neuroprotective in several ways.

Author(s): 
Tang, Bor Luen
Chua, Christelle En Lin
Publication Title: 
International Journal of Oncology

Telomeres are nucleoprotein structures at the ends of chromosomes that are composed of a repetitive G rich sequence and telomeric binding proteins. Telomeres prevent the degradation of chromosomal ends and protect against inappropriate recombination. Telomere attrition involves a tumor suppressor pathway that limits the replication of premalignant cells. The loss of telomeric DNA with each round of replication leads to growth arrest accompanied by senescence or apoptosis. Many tumor cells activate the telomerase gene to bypass senescence.

Author(s): 
Bojovic, Bojana
Crowe, David L.
Publication Title: 
Nature Communications

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97.

Author(s): 
Fujita, Kyota
Nakamura, Yoko
Oka, Tsutomu
Ito, Hikaru
Tamura, Takuya
Tagawa, Kazuhiko
Sasabe, Toshikazu
Katsuta, Asuka
Motoki, Kazumi
Shiwaku, Hiroki
Sone, Masaki
Yoshida, Chisato
Katsuno, Masahisa
Eishi, Yoshinobu
Murata, Miho
Taylor, J. Paul
Wanker, Erich E.
Kono, Kazuteru
Tashiro, Satoshi
Sobue, Gen
La Spada, Albert R.
Okazawa, Hitoshi
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington's disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-Cre(ERT2) mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97).

Author(s): 
Molero, Aldrin E.
Arteaga-Bracho, Eduardo E.
Chen, Christopher H.
Gulinello, Maria
Winchester, Michael L.
Pichamoorthy, Nandini
Gokhan, Solen
Khodakhah, Kamran
Mehler, Mark F.
Publication Title: 
The Journal of Biological Chemistry

The antimalarial drugs artemisinins have been described as inhibiting Ca(2+)-ATPase activity of PfATP6 (Plasmodium falciparum ATP6) after expression in Xenopus oocytes. Mutation of an amino acid residue in mammalian SERCA1 (Glu(255)) to the equivalent one predicted in PfATP6 (Leu) was reported to induce sensitivity to artemisinin in the oocyte system. However, in the present experiments, we found that artemisinin did not inhibit mammalian SERCA1a E255L either when expressed in COS cells or after purification of the mutant expressed in Saccharomyces cerevisiae.

Author(s): 
Cardi, Delphine
Pozza, Alexandre
Arnou, Bertrand
Marchal, Estelle
Clausen, Johannes D.
Andersen, Jens Peter
Krishna, Sanjeev
Møller, Jesper V.
le Maire, Marc
Jaxel, Christine
Publication Title: 
Science (New York, N.Y.)

Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class of antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4).

Author(s): 
Rottmann, Matthias
McNamara, Case
Yeung, Bryan K. S.
Lee, Marcus C. S.
Zou, Bin
Russell, Bruce
Seitz, Patrick
Plouffe, David M.
Dharia, Neekesh V.
Tan, Jocelyn
Cohen, Steven B.
Spencer, Kathryn R.
González-Páez, Gonzalo E.
Lakshminarayana, Suresh B.
Goh, Anne
Suwanarusk, Rossarin
Jegla, Timothy
Schmitt, Esther K.
Beck, Hans-Peter
Brun, Reto
Nosten, François
Renia, Laurent
Dartois, Veronique
Keller, Thomas H.
Fidock, David A.
Winzeler, Elizabeth A.
Diagana, Thierry T.
Publication Title: 
Malaria Journal

BACKGROUND: Drug resistance is a major problem to control Plasmodium falciparum infection in endemic countries. During last decade, African countries have changed first-line treatment to artemisinin-based combinations therapy (ACT); sulphadoxine-pyrimethamine (SP) is recommended for Intermittent Preventive Therapy (IPT). Molecular markers related to P falciparum resistance were analysed for the period of transition from SP to ACT, in isolates imported from Africa.

Author(s): 
Amor, Aranzazu
Toro, Carlos
Fernández-Martínez, Amalia
Baquero, Margarita
Benito, Agustín
Berzosa, Pedro
Publication Title: 
Malaria Journal

BACKGROUND: Anti-malarial drug resistance has emerged as one of the biggest challenges confronting the worldwide effort to control malaria. The appearance of chloroquine and multi-drug resistance had devastating effects on therapeutic efficacy of former first-line agents. Artemisinin has proven to be an excellent therapeutic alternative to fill the void in chemotherapeutic options left by resistance mechanisms. At the time of introduction, no resistance to artemisinins had been recorded, and artemisinins demonstrated excellent parasite reduction rates.

Author(s): 
Brasil, Larissa W.
Areas, André L. L.
Melo, Gisely C.
Oliveira, Cintia M. C.
Alecrim, Maria G. C.
Lacerda, Marcus V. G.
O'Brien, Connor
Oelemann, Walter M. R.
Zalis, Mariano G.
Publication Title: 
Molecular Vision

PURPOSE: To determine comparative effects of ultraviolet (UV)-A irradiation on structural and functional properties of wild type (WT) alphaB-crystallin and its three deamidated mutant proteins (alphaB-Asn78Asp, alphaB-Asn146Asp, and alphaB-Asn78/146Asp). METHODS: Three deamidated mutants previously generated from recombinant WT alphaB-crystallin, using a site-specific mutagenesis procedure as previously described [32], were used. The WT alphaB-crystallin and its three deamidated species were exposed to UV-A light (320-400 nm) at intensities of 20 or 50 J/cm(2).

Author(s): 
Mafia, Kerri
Gupta, Ratna
Kirk, Marion
Wilson, L.
Srivastava, O. P.
Barnes, Stephen
Publication Title: 
The Biochemical Journal

Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that activates transcription of a battery of cytoprotective genes by binding to the ARE (antioxidant response element). Nrf2 is repressed by the cysteine-rich Keap1 (kelch-like ECH-associated protein 1) protein, which targets Nrf2 for ubiquitination and subsequent degradation by a Cul3 (cullin 3)-mediated ubiquitination complex. We find that modification of Cys(151) of human Keap1, by mutation to a tryptophan, relieves the repression by Keap1 and allows activation of the ARE by Nrf2.

Author(s): 
Eggler, Aimee L.
Small, Evan
Hannink, Mark
Mesecar, Andrew D.

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