DyP-type peroxidases comprise a novel heme peroxidase family

Dye-decolorizing peroxidase (DyP) is produced by a basidiomycete (Thanatephorus cucumeris Dec 1) and is a member of a novel heme peroxidase family (DyP-type peroxidase family) that appears to be distinct from general peroxidases. Thus far, 80 putative members of this family have been registered in the PeroxiBase database (http://peroxibase.isbsib.ch/) and more than 400 homologous proteins have been detected via PSI-BLAST search. Although few studies have characterized the function and structure of these proteins, they appear to be bifunctional enzymes with hydrolase or oxygenase, as well as typical peroxidase activities. DyP-type peroxidase family suggests an ancient root compared with other general peroxidases because of their widespread distribution in the living world. In this review, firstly, an outline of the characteristics of DyP from T. cucumeris is presented and then interesting characteristics of the DyP-type peroxidase family are discussed. Received 14 October 2008; received after revision 12 November 2008; accepted 17 November 2008     

The perspectives of studying multi-domain protein folding

Most of fundamental studies on protein folding have been performed with small globular proteins consisting of a single domain. In vitro many of these proteins are well characterized by a reversible two-state folding scheme. However, the majority of proteins in the cell belong to the class of larger multi-domain proteins that often unfold irreversibly under in vitro conditions. This makes folding studies difficult or even impossible. In spite of these problems for many multi-domain proteins, folding has been investigated by classical refolding. Co-translational folding of nascent polypeptide chains when synthesized by ribosomes has also been studied. Single molecule techniques represent a promising approach for future studies on the folding of multi-domain proteins, and tremendous advances have been made in these techniques in recent years. In particular, fluorescence-based methods can contribute significantly to an understanding of the fundamental principles of multi-domain protein folding. Received 3 December 2008; accepted 23 December 2008     

Modulation of chemokine receptor activity through dimerization and crosstalk

Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors. Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking, development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed. Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics. Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008 C. L. Salanga, M. O’Hayre: These authors contributed equally.     

Welcome the Family of FANCJ-like Helicases to the Block of Genome Stability Maintenance Proteins

The FANCJ family of DNA helicases is emerging as an important group of proteins for the prevention of human disease, cancer, and chromosomal instability. FANCJ was identified by its association with breast cancer, and is implicated in Fanconi Anemia. Proteins with sequence similarity to FANCJ are important for maintenance of genomic stability. Mutations in genes encoding proteins related to FANCJ, designated ChlR1 in human and Chl1p in yeast, result in sister chromatid cohesion defects. Nematodes mutated in dog-1 show germline as well as somatic deletions in genes containing guanine-rich DNA. Rtel knockout mice are embryonic lethal, and embryonic stem cells show telomere loss and chromosomal instability. FANCJ also shares sequence similarity with human XPD and yeast RAD3 helicases required for nucleotide excision repair. The recently solved structure of XPD has provided new insight to the helicase core and accessory domains of sequence related Superfamily 2 helicases. The functions and roles of members of the FANCJ-like helicase family will be discussed. Received 17 September 2008; received after revision 24 October 2008; accepted 28 October 2008     

The BAG proteins: a ubiquitous family of chaperone regulators

The BAG (Bcl-2 associated athanogene) family is a multifunctional group of proteins that perform diverse functions ranging from apoptosis to tumorigenesis. An evolutionarily conserved group, these proteins are distinguished by a common conserved region known as the BAG domain. BAG genes have been found in yeasts, plants, and animals, and are believed to function as adapter proteins forming complexes with signaling molecules and molecular chaperones. In humans, a role for BAG proteins has been suggested in carcinogenesis, HIV infection, and Parkinson’s disease. These proteins are therefore potential therapeutic targets, and their expression in cells may serve as a predictive tool for such diseases. In plants, the Arabidopsis thaliana genome contains seven homologs of the BAG family, including four with domain organization similar to animal BAGs. Three members contain a calmodulin-binding domain possibly reflecting differences between plant and animal programmed cell death. This review summarizes current understanding of BAG proteins in both animals and plants. Received 21 November 2007; received after revision 17 December 2007; accepted 2 January 2008     

Protein-O-mannosyltransferases in virulence and development

Protein-O-mannosyltransferases (Pmt proteins) catalyse the addition of mannose to serine or threonine residues of secretory proteins. This modification was described first for yeast and later for other fungi, mammals, insects and recently also for bacteria. O-mannosylation depends on specific isoforms of the three Pmt1, 2 and 4 subfamilies. In fungi, O-mannosylation determines the structure and integrity of cell walls, as well as cellular differentiation and virulence. O-mannosylation of specific secretory proteins of the human fungal pathogen Candida albicans and of the bacterial pathogen Mycobacterium tuberculosis contributes significantly to virulence. In mammals and insects, Pmt proteins are essential for cellular differentiation and development, while lack of Pmt activity causes Walker-Warburg syndrome (muscular dystrophy) in humans. The susceptibility of human cells to certain viruses may also depend on O-mannosyl chains. This review focuses on the various roles of Pmt proteins in cellular differentiation, development and virulence. Received 6 September 2007; received after revision 3 October 2007; accepted 5 October 2007     

Signaling versus punching hole: How do Bacillus thuringiensis toxins kill insect midgut cells?

Cry proteins, produced by Bacillus thuringiensis (Bt), are widely used for the control of insect pests in agriculture as spray products or expressed in transgenic crops, such as maize and cotton. Little was known regarding the mechanism of action of these toxins when the first commercial Bt product was introduced fifty years ago. However, research on the mechanism of action over the last two decades has enhanced our knowledge of toxin interaction with membrane receptors and their effects in insect midgut cells. All this information allowed for the rational design of improved toxins with higher toxicity or toxins that overcome insect resistance, which could compromise Bt use and effectiveness in the field. In this review we discuss and evaluate the different models of the mode of action of Cry toxins, including a discussion about the role of various receptors in toxin action. Received 13 June 2008; received after revision 05 November 2008; accepted 11 November 2008     

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability. Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008     

Immunological determinants of the outcomes from primary hepatitis C infection

Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection, determined by a complex set of virus-host interactions. The focus of this review is the host mechanisms that facilitate clearance. Strong evidence points to characteristics of the cellular immune response as the key determinants of outcome, with evidence for the coordinated effects of the timing, magnitude, and breadth, as well as the intra-hepatic localisation of CD4+ and CD8+ T cell responses being critical. The recent discovery of viral evasion strategies targeting innate immunity suggests that interferon-stimulated gene products are also important. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals with acute HCV. Received 16 May 2008; received after revision 07 September 2008; accepted 30 September 2008     

Functions of reticulons in plants: What we can learn from animals and yeasts

Reticulons (RTNs) are membrane-spanning proteins sharing a typical domain named reticulon homology domain (RHD). RTN genes have been identified in all eukaryotic organisms examined so far, and the corresponding proteins have been found predominantly associated to the endoplasmic reticulum membranes. In animal and yeast, in which knowledge of the protein family is more advanced, RTNs are involved in numerous cellular processes such as apoptosis, cell division and intracellular trafficking. Up to now, a little attention has been paid to their plant counterparts, i.e., RTNLBs. In this review, we summarize the data available for RTNLB proteins and, using the data obtained with animal and yeast models, several functions for RTNLBs in plant cells are proposed and discussed. Received 01 July 2008; received after revision 08 September 2008; accepted 30 September 2008     

Mcl-1 is a potential therapeutic target in multiple types of cancer

Resistance to apoptosis is a common challenge in human malignancies contributing to both progress of cancer and resistance to conventional therapeutics. Abnormalities in a variety of cell intrinsic and extrinsic molecular mechanisms cooperatively promote tumor formation. Therapeutic approaches that specifically target components of these molecular mechanisms are getting widespread attention. Mcl-1 is a highly expressed pro-survival protein in human malignancies and its cellular expression is tightly regulated via multiple mechanisms. Mcl-1 differs from other members of the Bcl-2 family in having a very short half-life. So inhibition of its expression and/or neutralization of its anti-apoptotic function will rapidly make Mcl-1-dependent cells more susceptible to apoptosis and provide an opportunity to combat several types of cancers. This review summarizes the current knowledge on the regulation of Mcl-1 expression and discusses the alternative approaches targeting Mcl-1 in human cancer cells whose survivals mainly depend on Mcl-1. Received 6 October 2008; received after revision 21 October 2008; accepted 10 November 2008     

The continuing disappearance of “pure” Ca2+ buffers

Advances in the understanding of a class of Ca²⁺-binding proteins usually referred to as “Ca²⁺ buffers” are reported. Proteins historically embraced within this group include parvalbumins (α and β), calbindin-D9k, calbindin-D28k and calretinin. Within the last few years a wealth of data has accumulated that allow a better understanding of the functions of particular family members of the >240 identified EF-hand Ca²⁺-binding proteins encoded by the human genome. Studies often involving transgenic animal models have revealed that they exert their specific functions within an intricate network consisting of many proteins and cellular mechanisms involved in Ca²⁺ signaling and Ca²⁺ homeostasis, and are thus an essential part of the Ca²⁺ homeostasome. Recent results indicate that calbindin-D28k, possibly also calretinin and oncomodulin, the mammalian β parvalbumin, might have additional Ca²⁺ sensor functions, leaving parvalbumin and calbindin-D9k as the only “pure” Ca²⁺ buffers. Received 10 September 2008; received after revision 15 October 2008; accepted 4 November 2008