Cellular binding proteins for fatty acids and retinoids: similar or specialized functions?

The cellular fatty acid-binding proteins (FABP) and cellular retinoid (retinol, retinoic acid)-binding proteins (CRtBP) are structurally and functionally-defined groups within an evolutionarily conserved gene family. CRtBP are expressed in both fully differentiated and developing tissues in a manner that supports a relationship to the action of retinoic acid in morphogenesis and cellular differentiation. The FABP are, by contrast, expressed only in fully differentiated tissues in a manner compatible with a major function in the metabolism of long-chain fatty acids (LCFA) for energy production or storage. The precise function(s) of FABP and CRtBP remain imperfectly understood, while subspecialization of function(s) within the two groups is suggested by the complex diversity in both of structurally distinct members that display striking tissue and temporal specificity of expression in addition to ligand specificity. Notwithstanding this considerable apparent functional diversity among the FABP and CRtBP, available evidence supports a dual set of generic functions for both protein groups in a) promoting cellular flux of poorly water-soluble ligands and their subsequent metabolic utilization or transformation, and b) sequestration of ligands in a manner that limits their association with alternative binding sites within the cell, of which members of the steroid hormone nuclear receptor superfamily (HNR) are a potentially important category. Theoretical as well as experimental models probing diffusional fluxes of LCFAin vitro and in living cells have provided support for a function for FABP in intracellular LCFA transport. Protein-bound ligand also appears to provide the substrate for metabolic transformation of retinoids bound to CRtBP, but convincing evidence is lacking for an analogous mechanism in the direct facilitation of fatty acid utilization by FABP. An emerging relationship between FABP and CRtBP function centers on their binding of, and induction by, ligands which activate or transform specific HNR-the retinoic acid receptors and the peroxisome proliferator activated receptor in the case of CRtBP and FABP, respectively. Evidence consistent with both a promotive role (provision of ligands for HNR) and a protective role (limiting availability of free ligand for HNR association) has been advanced for CRtBP. Available data supports a protective function for cellular retinoic acid-binding proteins (CRABP) and liver FABP (L-FABP) and points to the existence of ligand-defined, lipid-binding-protein-HNR relationships in which CRABP serve to attenuate the induction of gene expression by retinoic acid, and in which L-FABP may modulate a cellular adaptive multigene response to increased LCFA flux or compromised LCFA utilization. Furthermore, the emerging role of LCFA in the regulation of gene expression combined with the complex interplay between heterologous HNR-ligand associations and gene cross-regulation implies an important potential interaction between FABP, CRtBP, and their respective ligands in gene regulation.Abbreviations A-FABP Adipocyte Fatty Acid-Binding Protein - CRABP Cellular Retinoic Acid-Binding Protein(s) - CRABP I Cellular Retinoic Acid-Binding Protein type I - CRABP II Cellular Retinoic Acid-Binding Protein type II - CRBP Cellular Retinol-Binding Protein(s) - CRBP Cellular Retinol-Binding Protein typy I - CRBP II Cellular Retinol-Binding Protein type II - CRtBP Cellular Retinoid-Binding Proteins - FABP Fatty Acid-Binding Protein - H-FABP Heart Fatty Acid-Binding Protein - HNR steroid Hormone-type Nuclear Receptor - I-FABP Intestinal Fatty Acid-Binding Protein - LCFA Long-Chain Fatty Acids - L-FABP Liver Fatty Acid-Binding Protein - NBD-stearate 12-(N-methyl)-N-(7-nitrobenzo-2-oxa-1,3,-diazol-4-yl)amino)-octadecanoic acid - PPAR Peroxisome Proliferator-Activated Receptor - RAR Retinoic Acid Receptor(s) - RARE Retinoic Acid Response Element - RXR Retinoic acid X Receptors(s) - RXRE Retinoic acid X Response Element     

Plant and animal transglutaminases: do similar functions imply similar structures?

In plants the post-translational modification of proteins by polyamines catalysed by transglutaminases has been studied since 1987; it was identified by the production of glutamyl-polyamine derivatives, biochemical features, recognition by animal antibodies and modification of typical animal substrates. Transglutaminases are widespread in all plant organs and cell compartments studied until now, chloroplast being the most studied. Substrates are: photosynthetic complexes and Rubisco in chloroplasts, cytoskeleton and cell wall proteins. Roles either specific of plants or in common with animals are related to photosynthesis, fertilisation, stresses, senescence and programmed cell death, showing that the catalytic function is conserved across the kingdoms. AtPng1p, the first plant transglutaminase sequenced shows undetectable sequence homology to the animal enzymes, except for the catalytic triad. It is, however, endowed with a calcium-dependent activity that allowed us to build a three-dimensional model adopting as a template the animal tranglutaminase 2.     

Plant and animal stem cells: conceptually similar, molecularly distinct?

Animals and plants maintain small pools of stem cells that continuously provide the precursors of more-specialized cells to sustain growth or to replace tissues. A comparison of plant and animal stem cells can highlight core aspects of stem-cell biology. In both types of organism, stem cells are maintained by intercellular signals that are available only in defined regions (niches) in the tissues. Although plants use different signals and are more flexible at establishing stem-cell niches in new locations, recent evidence suggests that the mechanisms restricting cell fate in stem-cell progeny are similar in both kingdoms and might pre-date the evolution of multicellular organisms.     

Stu2p and XMAP215: turncoat microtubule-associated proteins?

The dynamics of microtubule-based (MT) cytoskeletons are controlled by a variety of accessory proteins: microtubule-associated proteins (MAPs), which usually stabilize MTs, and microtubule-destabilizers. Two related MAPs, XMAP215 and Stu2p, are known to stabilize MTs. However, recent studies report that these proteins have a MT-destabilizing function as well. Here we discuss the implications of these reports.     

Nuclear and mitochondrial DNA repair: similar pathways?

Mitochondrial DNA (mtDNA) alterations are implicated in a broad range of human diseases and alterations of the mitochondrial genome are assumed to be a result of its high susceptibility to oxidative damage and its limited DNA repair compared to nuclear DNA (nDNA). Characterization of DNA repair mechanisms has generally focused on these processes in nDNA but increasing interest and research effort have contributed to our knowledge of the mechanisms underlying DNA repair in mitochondria. In this review, we make comparisons between nDNA and mtDNA repair pathways and propose a model for how these pathways interact in mitochondria.     

The enigma of the CLIC proteins: Ion channels, redox proteins, enzymes, scaffolding proteins?

Chloride intracellular channel proteins (CLICs) are distinct from most ion channels in that they have both soluble and integral membrane forms. CLICs are highly conserved in chordates, with six vertebrate paralogues. CLIC-like proteins are found in other metazoans. CLICs form channels in artificial bilayers in a process favoured by oxidising conditions and low pH. They are structurally plastic, with CLIC1 adopting two distinct soluble conformations. Phylogenetic and structural data indicate that CLICs are likely to have enzymatic function. The physiological role of CLICs appears to be maintenance of intracellular membranes, which is associated with tubulogenesis but may involve other substructures.     

The family feud: do proteins with similar structures fold via the same pathway?

Theoretical and experimental studies of protein folding have suggested that the topology of the native state may be the most important factor determining the folding pathway of a protein, independent of its specific amino acid sequence. To test this concept, many experimental studies have been carried out with the aim of comparing the folding pathways of proteins that possess similar tertiary structures, but divergent sequences. Many of these studies focus on quantitative comparisons of folding transition state structures, as determined by Phi(f) value analysis of folding kinetic data. In some of these studies, folding transition state structures are found to be highly conserved, whereas in others they are not. We conclude that folds displaying more conserved transition state structures may have the most restricted number of possible folding pathways and that folds displaying low transition state structural conservation possess many potential pathways for reaching the native state.     

Surfing, regulating and capturing: are all microtubule-tip-tracking proteins created equal?

A diverse group of microtubule-binding proteins has been linked through live-cell imaging of green fluorescent protein (GFP) fusion proteins. These proteins share the ability to associate with the plus ends of elongating microtubules and track with these tips as the microtubules grow, in a process known as \"tip tracking\". Several models have been proposed to explain the significance of this activity, including roles in delivering proteins to the cell periphery and in modulating microtubule dynamics. However, the recent observation that some of the tip trackers colocalize on structures undergoing search-capture suggests that tip tracking could be a fundamental aspect of the search-capture process. Focusing on the shared ability of these proteins to undergo tip tracking, this article is intended to place the search-capture model in the context of other proposed functions and to stimulate discussion in this area.     

Mitochondrial proton leak: a role for uncoupling proteins 2 and 3?

In mitochondria ATP synthesis is not perfectly coupled to oxygen consumption due to proton leak across the mitochondrial inner membrane. Quantitative studies have shown that proton leak contributes to approximately 25% of the resting oxygen consumption of mammals. Proton leak plays a role in accounting for differences in basal metabolic rate. Thyroid studies, body mass studies, phylogenic studies and obesity studies have all shown that increased mass-specific metabolic rate is linked to increased mitochondrial proton leak. The mechanism of the proton leak is unclear. Evidence suggests that proton leak occurs by a non-specific diffusion process across the mitochondrial inner membrane. However, the high degree of sequence homology of the recently cloned uncoupling proteins UCP 2 and UCP 3 to brown adipose tissue UCP 1, and their extensive tissue distribution, suggest that these novel uncoupling proteins play a role in proton leak. Early indications from reconstitution experiments and several in vitro expression studies suggest that the novel uncoupling proteins uncouple mitochondria. Furthermore, mice overexpressing UCP 3 certainly show a phenotype consistent with increased metabolism. The evidence for a role for these novel UCPs in mitochondrial proton leak is reviewed.     

Stress granules,RNA-binding proteins and polyglutamine diseases: too much aggregation?

Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present. Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders. This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.Subject terms: Neuroscience, Neurological disorders     

Anchoring proteins and cardiac sudden death: how and why?

Mutations in proteins responsible for ion transport in cardiac tissue can induce a destabilization of electrical function and provoke cardiac sudden death. Identification of a genetic anomaly in a French family that developed the syndrome of cardiac sudden death has revealed a crucial new element in normal cardiac electrical function : Ion channels need to be anchored to specific domains at the plasma membrane by an anchoring protein called ankyrin-B.     

Conformational distributions of denatured and unstructured proteins are similar to those of 20?×?20 blocked dipeptides

Understanding intrinsic conformational preferences of amino-acids in unfolded proteins is important for elucidating the underlying principles of their stability and re-folding on biological timescales. Here, to investigate the neighbor interaction effects on the conformational propensities of amino-acids, we carried out (1)H NMR experiments for a comprehensive set of blocked dipeptides and measured the scalar coupling constants between alpha protons and amide protons as well as their chemical shifts. Detailed inspection of these NMR properties shows that, irrespective of amino-acid side-chain properties, the distributions of the measured coupling constants and chemical shifts of the dipeptides are comparatively narrow, indicating small variances of their conformation distributions. They are further compared with those of blocked amino-acids (Ac-X-NHMe), oligopeptides (Ac-GGXGG-NH(2)), and native (lysozyme), denatured (lysozyme and outer membrane protein X from Escherichia coli), unstructured (Domain 2 of the protein 5A of Hepatitis C virus), and intrinsically disordered (hNlg3cyt: intracellular domain of human NL3) proteins. These comparative investigations suggest that the conformational preferences and local solvation environments of the blocked dipeptides are quite similar to not only those of other short oligopeptides but also those of denatured and natively unfolded proteins.     

Nuclear prostaglandin receptors: role in pregnancy and parturition?

The key regulatory role of prostanoids [prostaglandins (PGs) and thromboxanes (TXs)] in the maintenance of pregnancy and initiation of parturition has been established. However, our understanding of how these events are fine-tuned by the recruitment of specific signaling pathways remains unclear. Whereas, initial thoughts were that PGs were lipophilic and would easily cross cell membranes without specific receptors or transport processes, it has since been realized that PG signaling occurs via specific cell surface G-protein coupled receptors (GPCRs) coupled to classical adenylate cyclase or inositol phosphate signaling pathways. Furthermore, specific PG transporters have been identified and cloned adding a further level of complexity to the regulation of paracrine action of these potent bioactive molecules. It is now apparent that PGs also activate nuclear receptors, opening the possibility of novel intracrine signaling mechanisms. The existence of intracrine signaling pathways is further supported by accumulating evidence linking the perinuclear localization of PG synthesizing enzymes with intracellular PG synthesis. This review will focus on the evidence for a role of nuclear actions of PGs in the regulation of pregnancy and parturition.