Na+/Ca2+-K+ exchangers (NCKX): functional properties and physiological roles

The most numerous Ca2+ extrusion protein family, in terms of distinct genes, is the SLC24 gene family of Na+/Ca2+-K+ exchangers (NCKX). Five distinct gene products have been identified, mostly from specific animal excitable tissues such as neurons and smooth muscle, but also in places like skin pigment epithelium, signifying that NCKX proteins may play very specific roles, related to Ca2+ homeostasis, in these tissues. However, progress in elucidating the specific physiological roles of NCKX proteins has been slow in coming, largely because of challenges relating to isolating the activity of these proteins in their native tissues. Herein, we provide an overview of NCKX protein functional characteristics, highlighting properties that are unique and useful as distinguishing features over other Ca2+ handling mechanisms. We also present the first comprehensive review of the literature concerning physiological roles of NCKX proteins.     

CCN5: biology and pathophysiology

CCN5 is one of six proteins in the CCN family. This family of proteins has been shown to play important roles in many processes, including proliferation, migration, adhesion, extracellular matrix regulation, angiogenesis, tumorigenesis, fibrosis, and implantation. In this review, we focus on the biological and putative pathophysiological roles of CCN5. This intriguing protein is structurally unique among the CCN family members, and has a unique biological activity profile as well.     

S100 protein family and embryo implantation

It is well known that embryo implantation is a critical process in which embryo should be able to reach and attach to endometrium. Until now, various types of factors are involved in the regulation of this process. S100 proteins are calcium-binding proteins, which have vital roles in embryo implantation and have been considered as possible candidate markers for endometrial receptivity. However, studies regarding mode of actions of these proteins are scarce and more mechanistic insights are needed to clarify exact roles of each one of the S100 protein family. Understanding of function of these proteins in different compartments, stages, and phases of endometrium, could pave the way for conducting studies regarding the therapeutic significance of these proteins in some disorders such as recurrent implantation failure. In this review, we outlined roles and possible underlying mechanisms of S100 protein family in embryo implantation.     

Dead-box proteins: a family affair--active and passive players in RNP-remodeling

DEAD-box proteins are characterized by nine conserved motifs. According to these criteria, several hundreds of these proteins can be identified in databases. Many different DEAD-box proteins can be found in eukaryotes, whereas prokaryotes have small numbers of different DEAD-box proteins. DEAD-box proteins play important roles in RNA metabolism, and they are very specific and cannot mutually be replaced. In vitro, many DEAD-box proteins have been shown to have RNA-dependent ATPase and ATP-dependent RNA helicase activities. From the genetic and biochemical data obtained mainly in yeast, it has become clear that these proteins play important roles in remodeling RNP complexes in a temporally controlled fashion. Here, I shall give a general overview of the DEAD-box protein family.     

Characterization of the preprotein and amino acid transporter gene family in Arabidopsis

Seventeen loci encode proteins of the preprotein and amino acid transporter family in Arabidopsis (Arabidopsis thaliana). Some of these genes have arisen from recent duplications and are not in annotated duplicated regions of the Arabidopsis genome. In comparison to a number of other eukaryotic organisms, this family of proteins has greatly expanded in plants, with 24 loci in rice (Oryza sativa). Most of the Arabidopsis and rice genes are orthologous, indicating expansion of this family before monocot and dicot divergence. In vitro protein uptake assays, in vivo green fluorescent protein tagging, and immunological analyses of selected proteins determined either mitochondrial or plastidic localization for 10 and six proteins, respectively. The protein encoded by At5g24650 is targeted to both mitochondria and chloroplasts and, to our knowledge, is the first membrane protein reported to be targeted to mitochondria and chloroplasts. Three genes encoded translocase of the inner mitochondrial membrane (TIM)17-like proteins, three TIM23-like proteins, and three outer envelope protein16-like proteins in Arabidopsis. The identity of Arabidopsis TIM22-like proteins is most likely a protein encoded by At3g10110/At1g18320, based on phylogenetic analysis, subcellular localization, and complementation of a yeast (Saccharomyces cerevisiae) mutant and coexpression analysis. The lack of a preprotein and amino acid transporter domain in some proteins, localization in mitochondria, plastids, or both, variation in gene structure, and the differences in expression profiles indicate that the function of this family has diverged in plants beyond roles in protein translocation.     

Na+/Ca2+-K+ Exchangers (NCKX):Functional Properties and Physiological Roles

The most numerous Ca²⁺ extrusion protein family, in terms of distinct genes, is the SLC24 gene family of Na⁺/Ca²⁺-K⁺ exchangers (NCKX). Five distinct gene products have been identified, mostly from specific animal excitable tissues such as neurons and smooth muscle, but also in places like skin pigment epithelium, signifying that NCKX proteins may play very specific roles, related to Ca²⁺ homeostasis, in these tissues. However, progress in elucidating the specific physiological roles of NCKX proteins has been slow in coming, largely because of challenges relating to isolating the activity of these proteins in their native tissues. Herein, we provide an overview of NCKX protein functional characteristics, highlighting properties that are unique and useful as distinguishing features over other Ca²⁺ handling mechanisms. We also present the first comprehensive review of the literature concerning physiological roles of NCKX proteins.     

The role of BEACH proteins in Dictyostelium

The BEACH family of proteins is a novel group of proteins with diverse roles in eukaryotic cells. The identifying feature of these proteins is the BEACH domain named after the founding members of this family, the mouse beige and the human Chediak–Higashi syndrome proteins. Although all BEACH proteins share a similar structural organization, they appear to have very distinct cellular roles, ranging from lysosomal traffic to apoptosis and cytokinesis. Very little is currently known about the function of most of these proteins, few binding-partner proteins have been identified, and no molecular mechanism for any of these proteins has been discovered. Thus, it is important to establish good model systems for the study of these novel proteins. Dictyostelium contains six BEACH proteins that can be classified into four subclasses. Two of them, LvsA and LvsB, have clearly distinct roles in the cell. LvsA is localized on the contractile vacuole membrane and is essential for cytokinesis and osmoregulation. LvsB is most similar in sequence to the mammalian beige/Chediak–Higashi syndrome proteins and shares with them a common function in lysosomal trafficking. Structural and functional analysis of these proteins in Dictyostelium will help elucidate the function of this enigmatic novel family of proteins .     

TPR-containing proteins control protein organization and homeostasis for the endoplasmic reticulum

The endoplasmic reticulum (ER) is a complex, multifunctional organelle comprised of a continuous membrane and lumen that is organized into a number of functional regions. It plays various roles including protein translocation, folding, quality control, secretion, calcium signaling, and lipid biogenesis. Cellular protein homeostasis is maintained by a complicated chaperone network, and the largest functional family within this network consists of proteins containing tetratricopeptide repeats (TPRs). TPRs are well-studied structural motifs that mediate intermolecular protein–protein interactions, supporting interactions with a wide range of ligands or substrates. Seven TPR-containing proteins have thus far been shown to localize to the ER and control protein organization and homeostasis within this multifunctional organelle. Here, we discuss the roles of these proteins in controlling ER processes and organization. The crucial roles that TPR-containing proteins play in the ER are highlighted by diseases or defects associated with their mutation or disruption.     

TRIM family proteins: roles in proteostasis and neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer''s disease (AD), Parkinson''s disease (PD) and Huntington''s disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.     

The PsbP family of proteins

The PsbP family of proteins consists of 11 evolutionarily related thylakoid lumenal components. These include the archetypal PsbP protein, which is an extrinsic subunit of eukaryotic photosystem II, three PsbP-like proteins (CyanoP of the prokaryotic cyanobacteria and green oxyphotobacteria, and the PPL1 and PPL2 proteins found in many eukaryotes), and seven PsbP-domain (PPD) proteins (PPD1–PPD7, most of which are found in the green plant lineage). All of these possess significant sequence and structural homologies while having very diverse functions. While the PsbP protein has been extensively studied and plays a functional role in the optimization of photosynthetic oxygen evolution at physiological calcium and chloride concentrations, the molecular functions of the other family members are poorly understood. Recent investigations have begun to illuminate the roles that these proteins play in membrane protein complex assembly/stability, hormone biosynthesis, and other metabolic processes. In this review we have examined this functional information within the context of recent advances examining the structure of these components.     

杨树和葡萄UBX蛋白质家族分析

UBX（泛素调控X因子）蛋白质家族在泛素化相关的过程中起着重要的作用,如细胞周期调控、转录调控、信号转导、发育、胁迫响应、细胞程序性死亡、内吞作用和DNA修复。然而,到目前为止。UBX家族在杨树和葡萄中还没有被研究过。为了更好的弄清这两个植物的UBX家族,我们对UBX的基因结构、染色体位置、基因重复、系统发育关系作了分析。该研究对葡萄和杨树的UBX蛋白质家族作了第一个系统的分析。基因的外显子／内含子结构和蛋白质基序组成在同一个组里相对比较保守。基因重复分析表明．串联重复和片段重复对于杨树和葡萄的UBX基因家族的扩张有一定贡献,基因缺失在UBX基因家族的扩张过程中也发生了作用。本研究为UBX蛋白质功能的研究奠定了基础。     

Mechanisms of EHD/RME-1 protein function in endocytic transport

The evolutionarily conserved Eps15 homology domain (EHD)/receptor-mediated endocytosis (RME)-1 family of C-terminal EH domain proteins has recently come under intense scrutiny because of its importance in intracellular membrane transport, especially with regard to the recycling of receptors from endosomes to the plasma membrane. Recent studies have shed new light on the mode by which these adenosine triphosphatases function on endosomal membranes in mammals and Caenorhabditis elegans. This review highlights our current understanding of the physiological roles of these proteins in vivo, discussing conserved features as well as emerging functional differences between individual mammalian paralogs. In addition, these findings are discussed in light of the identification of novel EHD/RME-1 protein and lipid interactions and new structural data for proteins in this family, indicating intriguing similarities to the Dynamin superfamily of large guanosine triphosphatases.     

Olfactomedin Domain-Containing Proteins: Possible Mechanisms of Action and Functions in Normal Development and Pathology

A family of olfactomedin domain-containing proteins consists of at least 13 members in mammals. Although the first protein belonging to this family, olfactomedin, was isolated and partially characterized from frog olfactory neuroepithelim almost 20 years ago, the functions of many family members remain elusive. Most of the olfactomedin domain-containing proteins, similar to frog olfactomedin, are secreted glycoproteins that demonstrate specific expression patterns. Other family members are membrane-bound proteins that may serve as receptors. More than half of the olfactomedin domain-containing genes are expressed in neural tissues. Data obtained over the last several years demonstrate that olfactomedin domain-containing proteins play important roles in neurogenesis, neural crest formation, dorsal ventral patterning, cell–cell adhesion, cell cycle regulation, and tumorigenesis and may serve as modulators of critical signaling pathways (Wnt, bone morphogenic protein). Mutations in two genes encoding myocilin and olfactomedin 2 were implicated in glaucoma, and a growing number of evidence indicate that other genes belonging to the family of olfactomedin domain-containing proteins may contribute to different human disorders including psychiatric disorders. In this review, we summarize recent advances in understanding the possible roles of these proteins with special emphasis on the proteins that are preferentially expressed and function in neural tissues.     

Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling

In neurons, intracellular calcium signals have crucial roles in activating neurotransmitter release and in triggering alterations in neuronal function. Calmodulin has been widely studied as a Ca(2+) sensor that has several defined roles in neuronal Ca(2+) signalling, but members of the neuronal calcium sensor protein family have also begun to emerge as key components in a number of regulatory pathways and have increased the diversity of neuronal Ca(2+) signalling pathways. The differing properties of these proteins allow them to have discrete, non-redundant functions.     

Promotion and inhibition of cardiac hypertrophy by A-kinase anchor proteins

Originally identified as mediators of cyclic adenosine monophosphate (cAMP) and protein kinase A signaling, A-kinase anchor proteins (AKAPs) are now recognized as a diverse family of molecular scaffolds capable of interacting with many other proteins. Members of the AKAP family within the heart can take on either pro- or anti-hypertrophic roles by interacting with a myriad of protein kinases and phosphatases in the process. AKAPs often form the core of large signaling complexes (or signalosomes) that allow multiple pathways to converge and functionally intertwine. Approximately 30% of AKAPs discovered to date are expressed in the heart, but the functions of many of these remain to be discovered. This review focuses on AKAPs that have been demonstrated to play roles in mediating cardiac hypertrophy.     

Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal

The thrombospondins are a family of secreted, oligomeric glycoproteins that interact with cell surfaces, multiple components of the extracellular matrix, growth factors and proteases. These interactions underlie complex roles in cell interactions and tissue homeostasis in animals. Thrombospondins have been grouped functionally with SPARCs, tenascins and CCN proteins as adhesion-modulating or matricellular components of the extracellular milieu. Although all these multi-domain proteins share various commonalities of domains, the grouping is not based on structural homologies. Instead, the terms emphasise the general observations that these proteins do not form large-scale ECM structures, yet act at cell surfaces and function in coordination with the structural ECM and associated extracellular proteins. The designation of adhesion-modulation thus depends on observed tissue and cell culture ECM distributions and on experimentally identified functional properties. To date, the evolutionary relationships of these proteins have not been critically compared: yet, knowledge of their evolutionary histories is clearly relevant to any consideration of functional similarities. In this article, we survey briefly the structural and functional knowledge of these protein families, consider the evolution of each family, and outline a perspective on their functional roles.