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1.
The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical
receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory
proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified
that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein
subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic
cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein
subunits may therefore be considered as potential drug targets.
Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998 相似文献
2.
ROPs in the spotlight of plant signal transduction 总被引:7,自引:0,他引:7
Berken A 《Cellular and molecular life sciences : CMLS》2006,63(21):2446-2459
Small guanine nucleotide binding proteins of the Rho family called ROP play a crucial role as regulators of signal transduction
in plants. They participate in pathways that influence growth and development, and the adaptation of plants to various environmental
situations. As members of the Ras superfamily, ROPs function as molecular switches cycling between a GDP-bound ‘off’ and a
GTP-bound ‘on’ state in a strictly regulated manner. Latest research provided fascinating new insights into ROP regulation
by novel guanine nucleotide exchange factors, unconventional GTPase activating proteins, and guanine nucleotide dissociation
inhibitors, which apparently organize localized ROP activation. Important progress has also been made concerning signaling
components upstream and downstream of the ROP cycle involving receptor-like serine/threonine kinases and effectors that can
manipulate cytoskeletal dynamics, intracellular calcium levels, H2O2 production and further cellular targets. This review outlines the fast developing knowledge on ROP GTPases highlighting their
specific features, regulation and roles in a cellular signaling context.
Received 28 April 2006; received after revision 2 June 2006; accepted 29 June 2006 相似文献
3.
The application of fractal dimension-based constructs to probe the protein interior dates back to the development of the concept
of fractal dimension itself. Numerous approaches have been tried and tested over a course of (almost) 30 years with the aim
of elucidating the various facets of symmetry of self-similarity prevalent in the protein interior. In the last 5 years especially,
there has been a startling upsurge of research that innovatively stretches the limits of fractal-based studies to present
an array of unexpected results on the biophysical properties of protein interior. In this article, we introduce readers to
the fundamentals of fractals, reviewing the commonality (and the lack of it) between these approaches before exploring the
patterns in the results that they produced. Clustering the approaches in major schools of protein self-similarity studies,
we describe the evolution of fractal dimension-based methodologies. The genealogy of approaches (and results) presented here
portrays a clear picture of the contemporary state of fractal-based studies in the context of the protein interior. To underline
the utility of fractal dimension-based measures further, we have performed a correlation dimension analysis on all of the
available non-redundant protein structures, both at the level of an individual protein and at the level of structural domains.
In this investigation, we were able to separately quantify the self-similar symmetries in spatial correlation patterns amongst
peptide–dipole units, charged amino acids, residues with the π-electron cloud and hydrophobic amino acids. The results revealed
that electrostatic environments in the interiors of proteins belonging to ‘α/α toroid’ (all-α class) and ‘PLP-dependent transferase-like’
domains (α/β class) are highly conducive. In contrast, the interiors of ‘zinc finger design’ (‘designed proteins’) and ‘knottins’
(‘small proteins’) were identified as folds with the least conducive electrostatic environments. The fold ‘conotoxins’ (peptides)
could be unambiguously identified as one type with the least stability. The same analyses revealed that peptide–dipoles in
the α/β class of proteins, in general, are more correlated to each other than are the peptide–dipoles in proteins belonging
to the all-α class. Highly favorable electrostatic milieu in the interiors of TIM-barrel, α/β-hydrolase structures could explain
their remarkably conserved (evolutionary) stability from a new light. Finally, we point out certain inherent limitations of
fractal constructs before attempting to identify the areas and problems where the implementation of fractal dimension-based
constructs can be of paramount help to unearth latent information on protein structural properties. 相似文献
4.
Alastair S. Robertson Elizabeth Smythe Kathryn R. Ayscough 《Cellular and molecular life sciences : CMLS》2009,66(13):2049-2065
Endocytosis is a fundamental eukaryotic process required for remodelling plasma-membrane lipids and protein to ensure appropriate
membrane composition. Increasing evidence from a number of cell types reveals that actin plays an active, and often essential,
role at key endocytic stages. Much of our current mechanistic understanding of the endocytic process has come from studies
in budding yeast and has been facilitated by yeast’s genetic amenability and by technological advances in live cell imaging.
While endocytosis in metazoans is likely to be subject to a greater array of regulatory signals, recent reports indicate that
spatiotemporal aspects of vesicle formation requiring actin are likely to be conserved across eukaryotic evolution. In this
review we focus on the ‘modular’ model of endocytosis in yeast before highlighting comparisons with other cell types. Our
discussion is limited to endocytosis involving clathrin as other types of endocytosis have not been demonstrated in yeast. 相似文献
5.
Myelin basic protein: a multifunctional protein 总被引:1,自引:1,他引:0
Boggs JM 《Cellular and molecular life sciences : CMLS》2006,63(17):1945-1961
Myelin basic protein (MBP), the second most abundant protein in central nervous system myelin, is responsible for adhesion
of the cytosolic surfaces of multilayered compact myelin. A member of the ‘intrinsically disordered’ or conformationally adaptable
protein family, it also appears to have several other functions. It can interact with a number of polyanionic proteins including
actin, tubulin, Ca2+-calmodulin, and clathrin, and negatively charged lipids, and acquires structure on binding to them. It may act as a membrane
actin-binding protein, which might allow it to participate in transmission of extracellular signals to the cytoskeleton in
oligodendrocytes and tight junctions in myelin. Some size isoforms of MBP are transported into the nucleus and thus they may
also bind polynucleotides. Extracellular signals received by myelin or cultured oligodendrocytes cause changes in phosphorylation
of MBP, suggesting that MBP is also involved in signaling. Further study of this very abundant protein will reveal how it
is utilized by the oligodendrocyte and myelin for different purposes.
Received 2 March 2006; received after revision 12 April 2006; accepted 16 May 2006 相似文献
6.
Sánchez-Margalet V González-Yanes C Santos-Alvarez J Najib S 《Cellular and molecular life sciences : CMLS》1999,55(1):142-147
Insulin action is initiated by binding to its cognate receptor, which then triggers multiple cellular responses by activating
different signaling pathways. There is evidence that insulin receptor signaling may involve G protein activation in different
target cells. We have studied the activation of G proteins in rat hepatoma (HTC) cells. We found that insulin stimulated binding
of guanosine 5′-O-(3-thiotriphosphate) (GTP-γ-35S) to plasma membrane proteins of HTC cells, in a dose-dependent manner. This effect was completely blocked by pertussis toxin
treatment of the membranes, suggesting the involvement of G proteins of the Gα
i/Gα
o family. The expression of these Gα proteins was checked by Western blotting. Next, we used blocking antibodies to sort out the specific Gα protein activated by insulin stimulation. Anti-Gα
il,2 antibodies completely prevented insulin-stimulated GTP binding, whereas anti-Gα
o,i3 did not modify this effect of insulin on GTP binding. Moreover, we found physical association of the insulin receptor with
Gα
i1,2 by copurification studies. These results further support the involvement of a pertussis toxin-sensitive G protein in insulin
receptor signaling and provides some evidence of specific association and activation of Gα
i1,2 protein by insulin. These findings suggest that Gα
i1,2 proteins might be involved in insulin action.
Received 23 September 1998; received after revision 23 November 1998; accepted 25 November 1998 相似文献
7.
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor – a basally active GPCR 总被引:1,自引:0,他引:1
Kleinau G Jaeschke H Mueller S Worth CL Paschke R Krause G 《Cellular and molecular life sciences : CMLS》2008,65(22):3664-3676
Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications
are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated
receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant
mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling.
Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating
mutations (CAMs). Our results suggest that the conformation of a basally ‘silenced’ GPCR might impair its intrinsic capacity
for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR
models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details
underlying mutations decreasing basal activity.
G. Kleinau, H. Jaeschke: These two authors contributed equally to this work.
Received 31 July 2008; received after revision 12 September 2008; accepted 19 September 2008 相似文献
8.
In the early 1990s, the search for protein kinases led to the discovery of a novel family of non-receptor tyrosine kinases,
the Janus kinases or JAKs. These proteins were unusual because they contained two kinase homology domains and no other known
signaling modules. It soon became clear that these were not ‘just another’ type of kinase. Their ability to complement mutant
cells insensitive to interferons and to be activated by a variety of cytokines demonstrated their central signaling function.
Now, as we approach the end of the decade, it is evident from biochemical studies to knockout mice that JAKs play non-redundant
functions in development, differentiation, and host defense mechanisms. Here, recent progress is reviewed, with particular
emphasis on structure-function studies aimed at revealing how this family of tyrosine kinases is regulated. 相似文献
9.
Viero G Gropuzzo A Joubert O Keller D Prévost G Dalla Serra M 《Cellular and molecular life sciences : CMLS》2008,65(2):312-323
γ-Hemolysins are pore-forming toxins which develop from water-soluble monomers by combining two different ‘albeit homologous’
proteins. They form oligomeric pores in both cell and model membranes by undergoing a still poorly understood conformational
rearrangement in the stem region. The stem is formed by three β-strands, folded onto the core of the soluble protein and completely
extended in the pore. We propose a new model to explain such a process. Seven double-cysteine mutants were developed by inserting
one cysteine on the stretch that links the β-hairpin to the core of the protein and another on different positions along the
β-strands. The membrane bound protein was blocked in a non-lytic state by S–S bond formation. Six mutants were oxidized as
inactive intermediates, but became active after adding DTT. These results demonstrate that the stem extension can be temporarily
frozen and that the β-barrel formation occurs by β-strand concerted step-by-step sliding.
Received 22 October 2007; received after revision 15 November 2007; accepted 19 November 2007 相似文献
10.
Temussi PA 《Cellular and molecular life sciences : CMLS》2006,63(16):1876-1888
A few proteins, discovered mainly in tropical fruits, have a distinct sweet taste. These proteins have played an important
role towards a molecular understanding of the mechanisms of taste. Owing to the huge difference in size, between most sweeteners
and sweet proteins, it was believed that they must interact with a different receptor from that of small molecular weight
sweeteners. Recent modelling studies have shown that the single sweet taste receptor has multiple active sites and that the
mechanism of interaction of sweet proteins is intrinsically different from that of small sweeteners. Small molecular weight
sweeteners occupy small receptor cavities inside two subdomains of the receptor, whereas sweet proteins can interact with
the sweet receptor according to a mechanism called the ‘wedge model’ in which they bind to a large external cavity. This review
describes these mechanisms and outlines a history of sweet proteins.
Received 11 February 2006; received after revision 31 March 2006; accepted 11 May 2006 相似文献
11.
SNAREs and SNARE regulators in membrane fusion and exocytosis 总被引:21,自引:0,他引:21
J. E. Gerst 《Cellular and molecular life sciences : CMLS》1999,55(5):707-734
Eukaryotes have a remarkably well-conserved apparatus for the trafficking of proteins between intracellular compartments
and delivery to their target organelles. This apparatus comprises the secretory (or ‘protein export’) pathway, which is responsible
for the proper processing and delivery of proteins and lipids, and is essential for the derivation and maintenance of those
organelles. Protein transport between intracellular compartments is mediated by carrier vesicles that bud from one organelle
and fuse selectively with another. Therefore, organelle-specific trafficking of vesicles requires specialized proteins that
regulate vesicle transport, docking and fusion. These proteins are generically termed SNAREs and comprise evolutionarily conserved
families of membrane-associated proteins (i.e. the synaptobrevin/VAMP, syntaxin and SNAP-25 families) which mediate membrane
fusion. SNAREs act at all levels of the secretory pathway, but individual family members tend to be compartment-specific and,
thus, are thought to contribute to the specificity of docking and fusion events. In this review, we describe the different
SNARE families which function in exocytosis, as well as discuss the role of possible negative regulators (e.g. ‘SNARE-masters’)
in mediating events leading to membrane fusion. A model to illustrate the dynamic cycling of SNAREs between fusion-incompetent
and fusion-competent states, called the SNARE cycle, is presented.
Received 8 October 1998; received after revision 26 November 1998; accepted 26 November 1998 相似文献
12.
C. L. Salanga M. O’Hayre T. Handel 《Cellular and molecular life sciences : CMLS》2009,66(8):1370-1386
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. 相似文献
13.
Zinkernagel RM 《Cellular and molecular life sciences : CMLS》2012,69(10):1635-1640
So-called ‘immunological memory’ is, in my view, a typical example where a field of enquiry, i.e. to understand long-term
protection to survive reexposure to infection, has been overtaken by ‘l’art pour l’art’ of ‘basic immunology’. The aim of
this critical review is to point out some key differences between academic text book-defined immunological memory and protective
immunity as viewed from a co-evolutionary point of view, both from the host and the infectious agents. A key conclusion is
that ‘immunological memory’ of course exists, but only in particular experimental laboratory models measuring ‘quicker and
better’ responses after an earlier immunization. These often do correlate with, but are not the key mechanisms of, protection.
Protection depends on pre-existing neutralizing antibodies or pre-activated T cells at the time of infection—as documented
by the importance of maternal antibodies around birth for survival of the offspring. Importantly, both high levels of antibodies
and of activated T cells are antigen driven. This conclusion has serious implications for our thinking about vaccines and
maintaining a level of protection in the population to deal with old and new infectious diseases. 相似文献
14.
LDL receptor relatives at the crossroad of endocytosis and signaling 总被引:10,自引:0,他引:10
For many years, the low-density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP) have been considered to be prototypes of cargo receptors which deliver, via endocytosis, macromolecules into cells. However, the recent identification of additional members of this gene family and examination of their biology has revealed that at least some of these proteins are also signaling receptors. Very low density lipoprotein receptor and ApoER2 transmit the extracellular reelin signal into migrating neurons, and thus are key components of the reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. LRP5 and LRP6 are integral components of the Wnt signaling pathway which is central to many processes of metazoan development, cell proliferation, and tumor formation. Adaptor proteins interacting with the cytosolic domains of these receptors might orchestrate their ability to deliver their cargo or a signal. 相似文献
15.
Immunophilins: for the love of proteins 总被引:1,自引:0,他引:1
Barik S 《Cellular and molecular life sciences : CMLS》2006,63(24):2889-2900
Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity. This review summarizes our
knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric
dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP). The larger members of each family are modular
in nature, consisting of multiple PPIase and/or protein-protein interaction domains. Despite the apparent difference in their
sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions. Recent studies
have revealed that many immunophilins possess a chaperone function independent of PPIase activity. Knockout animal studies
have confirmed multiple essential roles of immunophilins in physiology and development. An immunophilin is indeed a natural
‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly.
Received: 7 May 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
16.
The mammalian olfactory system is not uniformly organized but consists of several subsystems each of which probably serves
distinct functions. Not only are the two major nasal chemosensory systems, the vomeronasal organ and the main olfactory epithelium,
structurally and functionally separate entities, but the latter is further subcompartimentalized into overlapping expression
zones and projection-related subzones. Moreover, the populations of ‘OR37’ neurons not only express a unique type of olfactory
receptors but also are segregated in a cluster-like manner and generally project to only one receptor-specific glomerulus.
The septal organ is an island of sensory epithelium on the nasal septum positioned at the nasoplatine duct; it is considered
as a ‘mini-nose’ with dual function. A specific chemosensory function of the most recently discovered subsystem, the so-called
Grueneberg ganglion, is based on the expression of olfactory marker protein and the axonal projections to defined glomeruli
within the olfactory bulb. This complexity of distinct olfactory subsystems may be one of the features determining the enormous
chemosensory capacity of the sense of smell. 相似文献
17.
Prochownik EV 《Cellular and molecular life sciences : CMLS》2005,62(21):2438-2459
The discovery of oncogenes (c-onc’s) and tumor suppressors (TS’s) has led to the concept that cancer arises from defects in
each of these classes of genes or their products. More recently, it has been appreciated that c-onc and TS proteins often
affect one another’s functions. Within this context, I review the two classical TS’s, p53 and the retinoblastoma protein,
and the consequences of their inactivation. The various forms of genomic instability (GI) that underly the high mutation rates
of transformed cells are then discussed. Particular emphasis is placed upon the concept that GI is not only an integral part
of the transformed state but is a prerequisite. Increased oxidative DNA damage, and/or an inabiliy to repair it, can lead
to GI. The review then discusses recent observations showing that loss of the TS protein peroxiredoxin 1 (prdx1) and increased
expression of the c-onc protein c-Myc, each leads to increased oxidative DNA damage. The critical nature of the c-onc-TS interaction
is underscored by that occurring between prdx1 and c-Myc, with the former protein regulating the production of DNA-damaging
reactive oxygen species by the latter. The intimate association between these proteins and others serves as a paradigm for
the exquisite balancing act that c-onc’s and TS’s must maintain in order to properly control normal DNA replication and cellular
proliferation while simultaneously minimizing the acquisition of potentially neoplastic mutations.
Received 10 May 2005; received after revision 3 July 2005; accepted 19 July 2005 相似文献
18.
Pocker Y 《Cellular and molecular life sciences : CMLS》2000,57(7):1008-1017
Water has been recognized as one of the major structuring factors in biological macromolecules. Indeed, water clusters influence
many aspects of biological function, and the water-protein interaction has long been recognized as a major determinant of
chain folding, conformational stability, internal dynamics, binding specificity and catalysis. I discuss here several themes
arising from recent progress in understanding structural aspects of ‘direct’ and ‘indirect’ ligands in terms of enzyme-substrate
interactions, and the role of water bridges in enzyme catalysis. The review also attempts to illuminate issues relating to
efficiency, through solvent interactions associated with enzymic specificity, and versatility. Over the years, carbonic anhydrase
(CA; carbonate hydro-lyase, EC 4.2.1.1) has played a significant role in the continuing delineation of principles underlying
the role of water in enzyme reactions. As a result of its pronounced catalytic power and robust constitution CA was transformed
into a veritable ‘laboratory’ in which active site mechanisms were rigorously tested and explored. 相似文献
19.
Courtois G 《Cellular and molecular life sciences : CMLS》2008,65(7-8):1123-1132
CYLD is a protein with tumor suppressor properties which was originally discovered associated with cylindromatosis, an inherited
cancer exclusively affecting the folicullo-sebaceous-apocrine unit of the epidermis. CYLD exhibits deubiquitinating activity
and acts as a negative regulator of NF-κB and JNK signaling through its interaction with NEMO and TRAF2. Recent data suggest
that this is unlikely to be its unique function in vivo. CYLD has also been shown to control other seemingly disparate cellular processes, such as proximal T cell receptor signaling,
TrkA endocytosis and mitosis. In each case, this enzyme appears to act by regulating a specific type of polyubiquitination,
K63 polyubiquitination, that does not result in recognition and degradation of proteins by the proteasome but instead controls
their activity through diverse mechanisms.
Received 6 October 2007; received after revision 2 November 2007; accepted 23 November 2007 相似文献
20.
Caltabiano G Campillo M De Leener A Smits G Vassart G Costagliola S Pardo L 《Cellular and molecular life sciences : CMLS》2008,65(16):2484-2492
The glycoprotein hormone receptor family is peculiar because, in contrast to other G protein-coupled receptors, a large N-terminal extracellular ectodomain is responsible for hormone recognition. Hormone-receptor pairs have evolved in such a manner that a limited number of positions both at the 'seat-belt' domain of the hormone and the leucine-rich repeats of the receptor, play attractive and repulsive interactions for binding and specificity, respectively. Surprisingly, the constitutive activity of the receptor, mostly modulated by highly conserved amino acids within the heptahelical domain of the receptor (i.e., outside the hormone binding region), also regulates effectiveness of hormone recognition by the extracellular part. In this review we analyze, at the molecular level, these important discriminating determinants for selective binding of glycoprotein hormones to their receptors, as well as natural mutations, observed in patients with gestational hyperthyroidism or ovarian hyperstimulation syndrome, that modify the selectivity of binding. 相似文献