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61.
Vincent Chaptal Michela Ottolia Gabriel Mercado-Besserer Debora A. Nicoll Kenneth D. Philipson Jeff Abramson 《The Journal of biological chemistry》2009,284(22):14688-14692
The mammalian Na+/Ca2+ exchanger, NCX1.1, serves as
the main mechanism for Ca2+ efflux across the sarcolemma following
cardiac contraction. In addition to transporting Ca2+, NCX1.1
activity is also strongly regulated by Ca2+ binding to two
intracellular regulatory domains, CBD1 and CBD2. The structures of both of
these domains have been solved by NMR spectroscopy and x-ray crystallography,
greatly enhancing our understanding of Ca2+ regulation.
Nevertheless, the mechanisms by which Ca2+ regulates the exchanger
remain incompletely understood. The initial NMR study showed that the first
regulatory domain, CBD1, unfolds in the absence of regulatory Ca2+.
It was further demonstrated that a mutation of an acidic residue involved in
Ca2+ binding, E454K, prevents this structural unfolding. A
contradictory result was recently obtained in a second NMR study in which
Ca2+ removal merely triggered local rearrangements of CBD1. To
address this issue, we solved the crystal structure of the E454K-CBD1 mutant
and performed electrophysiological analyses of the full-length exchanger with
mutations at position 454. We show that the lysine substitution replaces the
Ca2+ ion at position 1 of the CBD1 Ca2+ binding site and
participates in a charge compensation mechanism. Electrophysiological analyses
show that mutations of residue Glu-454 have no impact on Ca2+
regulation of NCX1.1. Together, structural and mutational analyses indicate
that only two of the four Ca2+ ions that bind to CBD1 are important
for regulating exchanger activity.Cardiac contraction/relaxation relies upon Ca2+ fluxes across
the plasma membrane (sarcolemma) of cardiomyocytes. Rapid Ca2+
influx (primarily through L-type Ca2+ channels) triggers the
release of additional Ca2+ from the sarcoplasmic reticulum
(SR),4 resulting in
cardiomyocyte contraction. Removal of cytosolic Ca2+ by reuptake
into the SR (through the SR Ca2+-ATPase) and expulsion from the
cell (primarily through the Na+/Ca2+ exchanger, NCX1.1)
results in relaxation (1).
Altered Ca2+ cycling is observed in a number of pathophysiological
situations including ischemia, hypertrophy, and heart failure
(2). Understanding the function
and regulation of NCX1.1 is thus of fundamental importance to understand
cardiac physiology.NCX1.1 utilizes the electrochemical potential of the Na+
gradient to extrude Ca2+ in a ratio of three Na+ ions to
one Ca2+ ion (3). In
addition to transporting both Na+ and Ca2+, NCX1.1 is
also strongly regulated by these two ions. Intracellular Na+ can
induce NCX1.1 to enter an inactivated state, whereas Ca2+ bound to
regulatory sites removes Na+-dependent inactivation and also
activates Na+/Ca2+ exchange
(3). These regulatory sites are
located on a large cytoplasmic loop (∼500 residues located between
transmembrane helices V and VI) containing two calcium binding domains (CBD1
and CBD2), which sense cytosolic Ca2+ levels. We have previously
shown that Ca2+ binding to the primary site in CBD2 is required for
full exchange regulation (4);
CBD1, however, is a site of higher affinity and appears to dominate the
activation of exchange activity by Ca2+.Both CBDs have an immunoglobulin fold formed from two antiparallel β
sheets generating a β sandwich with a differing number of Ca2+
ions coordinated at the tip of the domain
(4,
5). CBD1 binds four
Ca2+ ions, whereas CBD2 binds only two Ca2+ ions. An
initial NMR study revealed a local unfolding of the upper portion of CBD1 upon
release of Ca2+ (6).
In contrast, CBD2 did not display an unfolding response upon Ca2+
removal. A comparative analysis between CBDs revealed a difference in charge
at residues in equivalent positions near the Ca2+ coordination
site; Glu-454 in CBD1 is replaced by Lys-585 in CBD2. The unstructuring of
CBD1 upon Ca2+ removal was alleviated by reversing the charge of
the acidic residue (E454K) involved in Ca2+ coordination
(6). Previously, we solved the
structures of the Ca2+-bound and -free conformations of CBD2 and
revealed a charge compensation mechanism involving Lys-585
(4). The positively charged
lysine residue assumes the position of one of the Ca2+ ions upon
Ca2+ depletion, permitting CBD2 to retain its overall fold
(4). A similar phenomenon is
predicted to take place in E454K-CBD1 mutant. In addition, Hilge et
al. (6) showed that the
E454K mutation of CBD1 decreases Ca2+ affinity to a level similar
to that of CBD2 and suggested that the E454K mutation would cause the loss of
primary regulation of NCX1.1 by CBD1.The significance of some of these observations is unclear as a recent NMR
study (7) of CBD1 under more
physiologically relevant conditions revealed no significant alteration in
tertiary structure in the absence of Ca2+. It was hypothesized that
Ca2+ binding induces localized conformational and dynamic changes
involving several of the binding site residues. To clarify this issue, we
solved the crystal structure of the E454K-CBD1 mutant and examined the
functional effects of different CBD1 mutations in the full-length NCX1.1. The
results indicate that charge compensation is indeed provided by the residue
Lys-454 to replace one Ca2+, whereas the overall E454K-CBD1
structure is only slightly perturbed. The charge compensation, however, has no
impact on Ca2+ regulation of NCX1.1. 相似文献
62.
The intraspecific structure of the European anchovy (Engraulis encrasicolus) was studied on the basis of mitochondrial cytochrome b gene (cytb) fragment variability in 84 individuals from seven localities of the Black Sea and the Sea of Azov. The data on haplotype and nucleotide diversity and the values of neutrality tests suggested expansive growth of anchovy populations in the Azov-Black Sea basin. All samples from anchovy populations demonstrated a high level of haplotype diversity (Hd = 0.962). Two dominant haplotypes were identified, the frequencies of which were not directional, and they were present in all localities. Sequence analysis of the mitochondrial cytb gene fragment showed no differentiation between the Sea of Azov and the Black Sea subspecies. 相似文献
63.
64.
65.
James EA DeVoti JA Rosenthal DW Hatam LJ Steinberg BM Abramson AL Kwok WW Bonagura VR 《Journal of immunology (Baltimore, Md. : 1950)》2011,186(11):6633-6640
Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6) or HPV-11. Specific HLA-DR haplotypes DRB1*01:02 and DRB1*03:01 are associated with the development of RRP, disease severity, and Th2-like responses to HPV early proteins. Th1-like responses to HPV proteins have been shown to be protective in animal models. Therefore, we investigated the hypothesis that RRP patients have dysfunctional Th1-like, HPV-specific T cell responses. Using MHC class II tetramers, we identified immunogenic peptides within HPV-11 early proteins. Two distinct peptides (E6(113-132) and E2(1-20)) contained DRB1*01:02- or DRB1*03:01-restricted epitopes, respectively. An additional peptide (E2(281-300)) contained an epitope presented by both alleles. Peptide binding, tetramer, and proliferation assays identified minimal epitopes within these peptides. These epitopes elicited E2/E6-specific CD4(+) T cell responses in RRP patients and healthy control subjects, allowing the isolation of HPV-specific T cell lines using tetramers. The cytokine profiles and STAT signaling of these tetramer-positive T cells were measured to compare the polarization and responsiveness of HPV-specific T cells from patients with RRP and healthy subjects. HPV-specific IFN-γ secretion was substantially lower in T cells from RRP patients. HPV-specific IL-13 secretion was seen at modest levels in T cells from RRP patients and was absent in T cells from healthy control subjects. HPV-specific T cells from RRP patients exhibited reduced STAT-5 phosphorylation and reduced IL-2 secretion, suggesting anergy. Levels of STAT-5 phosphorylation and IFN-γ secretion could be improved through addition of IL-2 to HPV-specific T cell lines from RRP patients. Therapeutic vaccination or interventions aimed at restoring Th1-like cytokine responses to HPV proteins and reversing anergy could improve clinical outcomes for RRP patients. 相似文献
66.
Verónica A. Trivillin David B. Abramson Gaston E. Bumaguin Leandro J. Bruno Marcela A. Garabalino Andrea Monti Hughes Elisa M. Heber Sara Feldman Amanda E. Schwint 《Radiation and environmental biophysics》2014,53(4):635-643
Boron neutron capture synovectomy (BNCS) is explored for the treatment of rheumatoid arthritis (RA). The aim of the present study was to perform boron biodistribution studies in a model of antigen-induced arthritis (AIA) in female New Zealand rabbits, with the boron carriers boronophenylalanine (BPA) and sodium decahydrodecaborate (GB-10) to assess the potential feasibility of BNCS for RA. Rabbits in chronic phase of AIA were used for biodistribution studies employing the following protocols: intra-articular (ia) (a) BPA-f 0.14 M (0.7 mg 10B), (b) GB-10 (5 mg 10B), (c) GB-10 (50 mg 10B) and intravenous (iv), (d) BPA-f 0.14 M (15.5 mg 10B/kg), (e) GB-10 (50 mg 10B/kg), and (f) BPA-f (15.5 mg 10B/kg) + GB-10 (50 mg 10B/kg). At different post-administration times (13–85 min for ia and 3 h for iv), samples of blood, pathological synovium (target tissue), cartilage, tendon, muscle, and skin were taken for boron measurement by inductively coupled plasma mass spectrometry. The intra-articular administration protocols at <40 min post-administration both for BPA-f and GB-10, and intravenous administration protocols for GB-10 and [GB-10 + BPA-f] exhibited therapeutically useful boron concentrations (>20 ppm) in the pathological synovium. Dosimetric estimations suggest that BNCS would be able to achieve a therapeutically useful dose in pathological synovium without exceeding the radiotolerance of normal tissues in the treatment volume, employing boron carriers approved for use in humans. Radiobiological in vivo studies will be necessary to determine the actual therapeutic efficacy of BNCS to treat RA in an experimental model. 相似文献
67.
Vendela K. Lagerholm Edson Sandoval‐Castellanos Dorothee Ehrich Natalia I. Abramson Adam Nadachowski Daniela C. Kalthoff Mietje Germonpr Anders Angerbjrn John R. Stewart Love Daln 《Molecular ecology》2014,23(8):2060-2071
The Pleistocene glacial cycles resulted in significant changes in species distributions, and it has been discussed whether this caused increased rates of population divergence and speciation. One species that is likely to have evolved during the Pleistocene is the Norwegian lemming (Lemmus lemmus). However, the origin of this species, both in terms of when and from what ancestral taxon it evolved, has been difficult to ascertain. Here, we use ancient DNA recovered from lemming remains from a series of Late Pleistocene and Holocene sites to explore the species' evolutionary history. The results revealed considerable genetic differentiation between glacial and contemporary samples. Moreover, the analyses provided strong support for a divergence time prior to the Last Glacial Maximum (LGM), therefore likely ruling out a postglacial colonization of Scandinavia. Consequently, it appears that the Norwegian lemming evolved from a small population that survived the LGM in an ice‐free Scandinavian refugium. 相似文献
68.
Killer whales occur in Chilean waters, but their seasonality, diets, and overall distribution are poorly known. Here, we present data on group composition, site fidelity, and prey species of individual killer whales recorded in 63 sightings between 2004 and 2012 in the Chilean Patagonian fjords. Group sizes were small (mean = 5, SD = 2.5 for calf groups; mean = 3, SD = 1.5 for non-calf groups), and occurrence was significantly lower in summer months. Photographs enabled identification of 55 individuals from natural markings, and all resembled Southern Ocean type A killer whales. The species was transient in the area; the average presence was 1.7 days with 60 % of individuals seen only once. Occupancy was 3–44 days, and low levels of site fidelity were recorded (64 % of individuals were seen in only 1 year). Group composition at short time scales (3 months) remained stable, but we detected changes at longer time scales. Prey included fish, otariids, and seabirds. Twelve individual killer whales showed a broad dietary spectrum: 3 ate otariids and fish, 2 ate birds and otariids, and 7 ate otariids, birds, and possibly fish. Further research is needed to increase basic biological knowledge of these killer whales and to determine the relationship with type A killer whales from the Southern Ocean. 相似文献
69.
70.
Arthur M. Lesk Arun S. Konagurthu Lloyd Allison Maria Garcia de la Banda Peter J. Stuckey David Abramson 《Proteins》2020,88(12):1557-1558
We have modeled modifications of a known ligand to the SARS-CoV-2 (COVID-19) protease, that can form a covalent adduct, plus additional ligand-protein hydrogen bonds. 相似文献