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T. Jenuwein G. Laible R. Dorn G. Reuter 《Cellular and molecular life sciences : CMLS》1998,54(1):80-93
The SET domain is a 130-amino acid, evolutionarily conserved sequence motif present in chromosomal proteins that function
in modulating gene activities from yeast to mammals. Initially identified as members of the Polycomb- and trithorax-group (Pc-G and trx-G) gene families, which are required to maintain expression boundaries of homeotic selector (HOM-C) genes,
SET domain proteins are also involved in position-effect-variegation (PEV), telomeric and centromeric gene silencing, and
possibly in determining chromosome architecture. These observations implicate SET domain proteins as multifunctional chromatin
regulators with activities in both eu- and heterochromatin – a role consistent with their modular structure, which combines
the SET domain with additional sequence motifs of either a cysteine-rich region/zinc-finger type or the chromo domain. Multiple
functions for chromatin regulators are not restricted to the SET protein family, since many trx-G (but only very few Pc-G)
genes are also modifiers of PEV. Together, these data establish a model in which the modulation of chromatin domains is mechanistically
linked with the regulation of key developmental loci (e.g. HOM-C). 相似文献
3.
Epigenetic mechanisms in mammals 总被引:11,自引:1,他引:10
DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. Yet how methylation is propagated
and maintained between successive cell divisions is not fully understood. A series of enzyme families that can add methylation
marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. Apart from methyltransferases,
there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. Several
lysine and arginine demethylases have been discovered recently, and the presence of an active DNA demethylase is speculated
in mammalian cells. A mammalian methyl DNA binding protein MBD2 and de novo DNA methyltransferase DNMT3A and DNMT3B are shown experimentally to possess DNA demethylase activity. Thus, complex mammalian
epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during
mammalian development. 相似文献
4.
Juste Wesche Sarah Kühn Benedikt M. Kessler Maayan Salton Alexander Wolf 《Cellular and molecular life sciences : CMLS》2017,74(18):3305-3315
Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases. 相似文献
5.
DnaJ/Hsp40 (heat shock protein 40) proteins have been preserved throughout evolution and are important for protein translation,
folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of chaperone proteins, Hsp70s.
Because the ATP hydrolysis is essential for the activity of Hsp70s, DnaJ/Hsp40 proteins actually determine the activity of
Hsp70s by stabilizing their interaction with substrate proteins. DnaJ/Hsp40 proteins all contain the J domain through which
they bind to Hsp70s and can be categorized into three groups, depending on the presence of other domains. Six DnaJ homologs
have been identified in Escherichia coli and 22 in Saccharomyces cerevisiae. Genome-wide analysis has revealed 41 DnaJ/Hsp40 family members (or putative members) in humans. While 34 contain the typical
J domains, 7 bear partially conserved J-like domains, but are still suggested to function as DnaJ/ Hsp40 proteins. DnaJA2b,
DnaJB1b, DnaJC2, DnaJC20, and DnaJC21 are named for the first time in this review; all other human DnaJ proteins were dubbed
according to their gene names, e.g. DnaJA1 is the human protein named after its gene DNAJA1. This review highlights the progress
in studying the domains in DnaJ/Hsp40 proteins, introduces the mechanisms by which they interact with Hsp70s, and stresses
their functional diversity.
Received 27 April 2006; received after revision 5 June 2006; accepted 19 July 2006 相似文献
6.
Xiaoming Zhang Wisna Novera Yan Zhang Lih-Wen Deng 《Cellular and molecular life sciences : CMLS》2017,74(13):2333-2344
The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A–2D and 2F–2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates. MLL5 has been reported to play key roles in diverse biological processes, including cell cycle progression, genomic stability maintenance, adult hematopoiesis, and spermatogenesis. Recent studies of MLL5 variants and isoforms and putative MLL5 homologs in other species have enriched our understanding of the role of MLL5 in gene expression regulation, although the mechanism of action and physiological function of MLL5 remains poorly understood. In this review, we summarize recent research characterizing the structural features and biological roles of MLL5, and we highlight the potential implications of MLL5 dysfunction in human disease. 相似文献
7.
Even though every cell in a multicellular organism contains the same genes, the differing spatiotemporal expression of these
genes determines the eventual phenotype of a cell. This means that each cell type contains a specific epigenetic program that
needs to be replicated through cell divisions, along with the genome, in order to maintain cell identity. The stable inheritance
of these programs throughout the cell cycle relies on several epigenetic mechanisms. In this review, DNA methylation and histone
methylation by specific histone lysine methyltransferases (KMT) and the Polycomb/Trithorax proteins are considered as the
primary mediators of epigenetic inheritance. In addition, non-coding RNAs and nuclear organization are implicated in the stable
transfer of epigenetic information. Although most epigenetic modifications are reversible in nature, they can be stably maintained
by self-recruitment of modifying protein complexes or maintenance of these complexes or structures through the cell cycle. 相似文献
8.
The small heat shock proteins and their clients 总被引:11,自引:0,他引:11
Small heat shock proteins are ubiquitous proteins found throughout all kingdoms. One of the most notable features is their
large oligomeric structures with conserved structural organization. It is well documented that small heat shock proteins can
capture unfolding proteins to form stable complexes and prevent their irreversible aggregation. In addition, small heat shock
proteins coaggregate with aggregation-prone proteins for subsequent, efficient disaggregation of the protein aggregates. The
release of substrate proteins from the transient reservoirs, i.e. complexes and aggregates with small heat shock proteins,
and their refolding require cooperation with ATP-dependent chaperone systems. The amphitropic small heat shock proteins were
shown to associate with membranes, although they do not contain transmembrane domains or signal sequences. Recent studies
indicate that small heat shock proteins play an important role in membrane quality control and thereby potentially contribute
to the maintenance of membrane integrity especially under stress conditions.
Received 11 July 2006; received after revision 4 October 2006; accepted 10 November 2006 相似文献
9.
MurNAc etherases cleave the uniqued-lactyl ether bond of the bacterial cell wall sugar N-acetylmuramic acid (MurNAc). Members of this newly discovered family of enzymes are widely distributed among bacteria and
are required to utilize peptidoglycan fragments obtained either from the environment or from the endogenous cell wall (i.e.,
recycling). MurNAc etherases are strictly dependent on the substrate MurNAc possessing a free reducing end and a phosphoryl
group at C6. They carry a single conserved sugar phosphate isomerase/sugar phosphate- binding (SIS) domain to which MurNAc
6-phosphate is bound. Two subunits form an enzymatically active homodimer that structurally resembles the isomerase module
of the double-SIS domain protein GlmS, the glucosamine 6-phosphate synthase. Structural comparison provides insights into
the two-step lyase-type reaction mechanism of MurNAc etherases: β-elimination of the D-lactic acid substituent proceeds through
a 2,3-unsaturated sugar intermediate to which water is subsequently added.
Received 31 August 2007; received after revision 12 October 2007; accepted 1 November 2007 相似文献
10.
Hairpin RNA: a secondary structure of primary importance 总被引:4,自引:0,他引:4
An RNA hairpin is an essential secondary structure of RNA. It can guide RNA folding, determine interactions in a ribozyme,
protect messenger RNA (mRNA) from degradation, serve as a recognition motif for RNA binding proteins or act as a substrate
for enzymatic reactions. In this review, we have focused on cis-acting RNA hairpins in metazoa, which regulate histone gene expression, mRNA localization and translation. We also review
evolution, mechanism of action and experimental use of trans-acting microRNAs, which are coded by short RNA hairpins. Finally, we discuss the existence and effects of long RNA hairpin
in animals. We show that several proteins previously recognized to play a role in a specific RNA stem-loop function in cis were also linked to RNA silencing pathways where a different type of hairpin acts in trans. Such overlaps indicate that the relationship between certain mechanisms that recognize different types of RNA hairpins is
closer than previously thought.
Received 21 November 2005; received after revision 3 January 2006; accepted 11 January 2006 相似文献
11.
This review describes the structure and function of prolyl endopeptidase (PEP) enzymes and how they are being evaluated as
drug targets and therapeutic agents. The most well studied PEP family has a two-domain structure whose unique seven-blade
β-propeller domain works with the catalytic domain to hydrolyze the peptide bond on the carboxyl side of internal proline
residues of an oligopeptide substrate. Structural and functional studies on this protease family have elucidated the mechanism
for peptide entry between the two domains. Other structurally unrelated PEPs have been identified, but have not been studied
in detail. Human PEP has been evaluated as a pharmacological target for neurological diseases due to its high brain concentration
and ability to cleave neuropeptides in vitro. Recently, microbial PEPs have been studied as potential therapeutics for celiac sprue, an inflammatory disease of the small
intestine triggered by proline-rich gluten.
Received 6 July 2006; received after revision 17 August 2006; accepted 1 November 2006 相似文献
12.
Melanija Posavec Gyula Timinszky Marcus Buschbeck 《Cellular and molecular life sciences : CMLS》2013,70(9):1509-1524
How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite-binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD+-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function. 相似文献
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A. Shukla P. Chaurasia S. R. Bhaumik 《Cellular and molecular life sciences : CMLS》2009,66(8):1419-1433
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 相似文献
15.
Emerging connections between DNA methylation and histone acetylation 总被引:18,自引:0,他引:18
Modifications of both DNA and chromatin can affect gene expression and lead to gene silencing. Evidence of links between
DNA methylation and histone hypoacetylation is accumulating. Several proteins that specifically bind to methylated DNA are
associated with complexes that include histone deacetylases (HDACs). In addition, DNA methyltransferases of mammals appear
to interact with HDACs. Experiments with animal cells have shown that HDACs are responsible for part of the repressive effect
of DNA methylation. Evidence was found in Neurospora that protein acetylation can in some cases affect DNA methylation. The available data suggest that the roles of DNA methylation
and histone hypoacetylation, and their relationship with each other, can vary, even within an organism. Some open questions
in this emerging field that should be answered in the near future are discussed. 相似文献
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Dynamic protein methylation in chromatin biology 总被引:1,自引:1,他引:0
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Stirnimann CU Grütter MG Glockshuber R Capitani G 《Cellular and molecular life sciences : CMLS》2006,63(14):1642-1648
DsbD is a redox-active protein of the inner Escherichia coli membrane possessing an N-terminal (nDsbD) and a C-terminal (cDsbD) periplasmic domain. nDsbD interacts with four different
redox proteins involved in the periplasmic disulfide isomerization and in the cytochrome c maturation systems. We review here the studies that led to the structural characterization of all soluble DsbD domains involved
and, most importantly, of trapped disulfide intermediate complexes of nDsbD with three of its four redox partners. These results
revealed the structural features enabling nDsbD, a ‘redox hub’ with an immunoglobulin-like fold, to interact efficiently with
its different thioredoxin-like partners.
Received 3 February 2006; received after revision 1 March 2006; accepted 5 April 2006 相似文献
20.
Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA (mRNA) structures, signaling
pathways and protein catalysts. Ferritin, a protein nanocage around an iron/oxy mineral, centralizes the control. Complementary
DNA (antioxidant responsive element/Maf recognition element) and mRNA (iron responsive element) responses regulate ferritin
synthesis rates. Multiple iron-protein interactions control iron and oxygen substrate movement through the protein cage, from
dynamic gated pores to catalytic sites related to di-iron oxygenase cofactor sites. Maxi-ferritins concentrate iron for the
bio-synthesis of iron/heme proteins, trapping oxygen; bacterial mini-ferritins, DNA protection during starvation proteins,
reverse the substrate roles, destroying oxidants, trapping iron and protecting DNA. Ferritin is nature’s unique and conserved
approach to controlled, safe use of iron and oxygen, with protein synthesis in animals adjusted by dual, genetic DNA and mRNA
sequences that selectively respond to iron or oxidant signals and link ferritin to proteins of iron, oxygen and antioxidant
metabolism.
Received 25 June 2005; received after revision 17 October 2005; accepted 25 November 2005 相似文献