Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The basic chromosomal protein histone H1 binds avidly to liposomes containing acidic phospholipids and with characteristics somewhat resembling the lipid association of cytochrome c (cyt c) [Koiv et al. (1995) Biochemistry 34, 8018-8027]. Membrane association of histone H1 strongly attenuates the lipid lateral diffusion in large unilamellar vesicles containing phosphatidylglycerol (PG) as revealed by the decrease in the excimer to monomer ratio Ie/Im of the pyrene fatty acid-containing phospholipid derivative 1-palmitoyl-2-[10-(pyren-1-yl)decanoyl]-sn-glycero-3-phosphogly cer ol (PPDPG) fluorescence. Similarly, an increase in fluorescence anisotropy of the membrane-incorporated probe, diphenylhexatriene (DPH), due to histone H1 indicates that the membrane becomes more rigid. Increasing the mole fraction of PG (XPG) increases in a linear manner the concentration [H1]s required for the maximal decrease in Ie/Im or increase in fluorescence anisotropy, thus allowing to estimate the binding site for H1 to be constituted by approximately 20 PG molecules. Domain formation is also supported by differential scanning calorimetry measurements. Subsequently, we studied the detachment of cyt c from PG-containing liposomes by H1 by measuring its efficiency in decreasing resonance energy transfer between PPDPG and the heme of cyt c. The A-site interaction of 1 microM cyt c with 25 microM PG/PC (XPG = 0.20) liposomes is fully inhibited by low (0.1 microM) histone concentrations. Upon XPG being increased, the concentration [H1]D required for complete detachment of cyt c increases. Irrespective of the [cyt c] present (varying between 0.1 and 10 microM), the C-site-mediated binding of cyt c to neat PG liposomes (XPG = 1.0) is fully prevented at [H1] = 0.6 microM. These measurements indicate that the affinity of histone H1 to liposomes exceeds that of cyt c. The above effects of H1 were subsequently compared with those of different basic membrane-associating peptides. Notably, the effects of HI were remarkably well-reproduced by polylysine (K19). The high affinity of H1 to acidic phospholipids suggests that this feature might also contribute to its physiological function.
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PMID:Dissociation of cytochrome c from liposomes by histone H1. Comparison with basic peptides. 860 3

Membrane association and detachment of cytochrome c (cyt c) in millisecond to second time domain were investigated by stopped-flow fluorescence spectroscopy monitoring the efficiency of energy transfer from a pyrene-fatty acid containing phospholipid derivative, 1-palmitoyl-2-[10-(pyren-1-yl)-decanoyl]-sn-glycero-3-phosphoglyce rol (PPDPG, mole fraction X = 0.01) to the heme of the cyt c. Large unilamellar liposomes composed of egg phosphatidylcholine (eggPC) with varying content of the acidic phospholipid phosphatidylglycerol (eggPG) were employed. Unexpectedly, the rate of binding of cyt c to membranes was attenuated upon increasing the mole fraction of the acidic phospholipid (XPG). For example, at 50 microM phospholipid and 5 microM cyt c, when XPG was increased from 0.20 to 0.40 the half-time for the single-exponential decay in fluorescence increased from 4.7 to 8.6 ms. A similar observation was made for the membrane binding of another cationic protein, histone H1. We suggest that the formation of cooperative hydrogen-bonded networks by deprotonated and protonated PG in the vesicle surface retards the binding of cyt c to the liposome surface. However, once formed, the complex of cyt c with acidic phospholipids is stabilized by increasing XPG. Accordingly, significantly prolonged half-times of dissociation of cyt c from liposomes by NaCl, ATP, and different cationic proteins are measured upon increasing XPG. Differences between the latter cationic membrane binding ligands most likely reflect the varying relative contributions of hydrophobicity and Coulombic forces to their attachment to liposomes. Our data on the release and binding of cyt c to liposomes as a function of XPG and in the presence of ATP also provide the first direct experimental evidence for multiple lipid binding sites in cyt c.
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PMID:Binding and dissociation of cytochrome c to and from membranes containing acidic phospholipids. 947 68

A stopped-flow spectrofluorometer equipped with a rapid scanning emission monochromator was utilized to monitor the binding of adriamycin to phospholipid liposomes. The latter process is evident as a decrease in fluorescence emission from a trace amount of a pyrene-labeled phospholipid analog (PPDPG, 1-palmitoyl-2-[(6-pyren-1-yl)]decanoyl-sn-glycero-3-phospho-rac-++ +glyce rol) used as a donor for resonance energy transfer to adriamycin. For zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes, fluorescence decay was slow, with a half-time t1/2 of approximately 2 s. When the mole fraction of the acidic phospholipid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-rac-glycerol (POPG), was increased to XPG >/= 0.04, the decay of fluorescence became double exponential, and an additional, significantly faster process with t1/2 in the range between 2 and 4 ms was observed. Subsequently, as XPG was increased further, the amplitude of the fast process increased, whereas the slower process was attenuated, its t1/2 increasing to 20 s. Increasing [NaCl] above 50 mM or [CaCl2] above 150 microM abolished the fast component, thus confirming this interaction to be electrostatic. The critical dependence of the fast component on XPG allows the use of this process to probe the organization of acidic phospholipids in liposomes. This was demonstrated with 1, 2-palmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes incorporating PPDPG (XPPDPG = 0.03), i.e., conditions where XPG in fluid bilayers is below the required threshold yielding the fast component. In keeping with the presence of clusters of PPDPG, the fast component was observed for gel-state liposomes. At approximately 34 degreesC (i.e., 6 degrees below Tm), the slower fluorescence decay also appeared, and it was seen throughout the main phase transition region as well as in the liquid-crystalline state. The fluorescence decay behavior at temperatures below, above, and at the main phase transition temperature is interpreted in terms of thermal density fluctuations and an intermediate state between gel and liquid-crystalline states being involved in the phospholipid main phase transition. This is the first observation of a cluster constituted by acidic phospholipids controlling the membrane association of a drug.
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PMID:Binding of adriamycin to liposomes as a probe for membrane lateral organization. 992 91

Xeroderma pigmentosum (XP) patients exhibit a 1000-fold increased risk for developing skin cancers including malignant melanoma. We investigated the role of three variant alleles of the DNA repair gene XPC and one variant allele of the XPG gene in a hospital-based case-control study of 294 Caucasian patients from Germany with malignant melanoma and 375 healthy control individuals from the same area matched by sex. The polymorphisms G1580A (XPC exon 8; Arg492His), T1601C (XPC exon 8; Val499Ala), G2166A (XPC exon 10; Arg687Arg), and C3507G (XPG exon 15; Asp1104His) were not in linkage disequilibrium. The allele frequencies (cases: controls) were for 1580A 6.29%: 5.63%, for 1601C 79.08%: 78.28%, for 2166A 26.19%: 28.13%, and for 3507G 79.86%: 78.61%. We found no association of the homozygous 1580A, 1601C, 2166A, and 3507G genotypes with increased risks of melanoma: OR 1.254 (95% CI: 0.486-3.217), OR 1.108 (95% CI: 0.629-1.960), OR 0.817 (95% CI: 0.490-1.358), and OR 1.168 (95% CI: 0.670-2.044), respectively. Exploratory analyses of subgroups of melanoma patients compared to all controls indicated no association of these genotypes with increased risks for development of multiple primary melanomas (n = 28), a negative family history for melanoma (n = 277), melanomas in individuals with a low number of nevi (n = 273), melanomas in individuals older than 55 years (n = 142), and melanomas thicker than 1 mm (n = 126).
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PMID:No association between three xeroderma pigmentosum group C and one group G gene polymorphisms and risk of cutaneous melanoma. 1549 39