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101.
Hodkinson PS Elliott PA Lad Y McHugh BJ MacKinnon AC Haslett C Sethi T 《The Journal of biological chemistry》2007,282(39):28991-29001
102.
103.
Heena V. Lad Lin Liu José L. Payá-Cano Cathy Fernandes Leonard C. Schalkwyk 《Mammalian genome》2007,18(6-7):482-491
Immobility in the tail suspension test (TST) is considered a model of despair in a stressful situation, and acute treatment
with antidepressants reduces immobility. Inbred strains of mouse exhibit widely differing baseline levels of immobility in
the TST and several quantitative trait loci (QTLs) have been nominated. The labor of manual scoring and various scoring criteria
make obtaining robust data and comparisons across different laboratories problematic. Several studies have validated strain
gauge and video analysis methods by comparison with manual scoring. We set out to find objective criteria for automated scoring
parameters that maximize the biological information obtained, using a video tracking system on tapes of tail suspension tests
of 24 lines of the BXD recombinant inbred panel and the progenitor strains C57BL/6J and DBA/2J. The maximum genetic effect
size is captured using the highest time resolution and a low mobility threshold. Dissecting the trait further by comparing
genetic association of multiple measures reveals good evidence for loci involved in immobility on chromosomes 4 and 15. These
are best seen when using a high threshold for immobility, despite the overall better heritability at the lower threshold.
A second trial of the test has greater duration of immobility and a completely different genetic profile. Frequency of mobility
is also an independent phenotype, with a distal chromosome 1 locus.
Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users. 相似文献
104.
A R Walmsley M R Batten U Lad N J Bulleid 《The Journal of biological chemistry》1999,274(21):14884-14892
The correct folding and assembly of proteins within the endoplasmic reticulum (ER) are prerequisites for subsequent transport from this organelle to the Golgi apparatus. The mechanisms underlying the ability of the cell to recognize and retain unassembled or malfolded proteins generally require binding to molecular chaperones within the ER. One classic example of this process occurs during the biosynthesis of procollagen. Here partially folded intermediates are retained and prevented from secretion, leading to a build up of unfolded chains within the cell. The accumulation of these partially folded intermediates occurs during vitamin C deficiency due to incomplete proline hydroxylation, as vitamin C is an essential co-factor of the enzyme prolyl 4-hydroxylase. In this report we show that this retention is tightly regulated with little or no secretion occurring under conditions preventing proline hydroxylation. We studied the molecular mechanism underlying retention by determining which proteins associate with partially folded procollagen intermediates within the ER. By using a combination of cross-linking and sucrose gradient analysis, we show that the major protein binding to procollagen during its biosynthesis is prolyl 4-hydroxylase, and no binding to other ER resident proteins including Hsp47 was detected. This binding is regulated by the folding status rather than the extent of hydroxylation of the chains demonstrating that this enzyme can recognize and retain unfolded procollagen chains and can release these chains for further transport once they have folded correctly. 相似文献
105.
Substrate binding and catalytic mechanism in ascorbate peroxidase: evidence for two ascorbate binding sites 总被引:1,自引:0,他引:1
The catalytic mechanism of recombinant soybean cytosolic ascorbate peroxidase (rsAPX) and a derivative of rsAPX in which a cysteine residue (Cys32) located close to the substrate (L-ascorbic acid) binding site has been modified to preclude binding of ascorbate [Mandelman, D., Jamal, J., and Poulos, T. L. (1998) Biochemistry 37, 17610-17617] has been examined using pre-steady-state and steady-state kinetic techniques. Formation (k1 = 3.3 +/- 0.1 x 10(7) M(-1) s(-1)) of Compound I and reduction (k(2) = 5.2 +/- 0.3 x 10(6) M(-1) s(-1)) of Compound I by substrate are fast. Wavelength maxima for Compound I of rsAPX (lambda(max) (nm) = 409, 530, 569, 655) are consistent with a porphyrin pi-cation radical. Reduction of Compound II by L-ascorbate is rate-limiting: at low substrate concentration (0-500 microM), kinetic traces were monophasic but above approximately 500 microM were biphasic. Observed rate constants for the fast phase overlaid with observed rate constants extracted from the (monophasic) dependence observed below 500 microM and showed saturation kinetics; rate constants for the slow phase were linearly dependent on substrate concentration (k(3-slow)) = 3.1 +/- 0.1 x 10(3) M(-1) s(-1)). Kinetic transients for reduction of Compound II by L-ascorbic acid for Cys32-modified rsAPX are monophasic at all substrate concentrations, and the second-order rate constant (k(3) = 0.9 +/- 0.1 x 10(3) M(-1) s(-1)) is similar to that obtained from the slow phase of Compound II reduction for unmodified rsAPX. Steady-state oxidation of L-ascorbate by rsAPX showed a sigmoidal dependence on substrate concentration and data were satisfactorily rationalized using the Hill equation; oxidation of L-ascorbic acid by Cys32-modified rsAPX showed no evidence of sigmoidal behavior. The data are consistent with the presence of two kinetically competent binding sites for ascorbate in APX. 相似文献
106.
Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis 总被引:29,自引:0,他引:29
107.
Dr. Lad Čelakovský 《Plant Systematics and Evolution》1890,40(7):255-259
Ohne Zusammenfassung 相似文献
108.
The N-terminal domains of talin cooperate with the phosphotyrosine binding-like domain to activate beta1 and beta3 integrins 总被引:3,自引:0,他引:3
The activation of integrin adhesion receptors from low to high affinity in response to intracellular cues controls cell adhesion and signaling. Binding of the cytoskeletal protein talin to the beta3 integrin cytoplasmic tail is required for beta3 activation, and the integrin-binding PTB-like F3 domain of talin is sufficient to activate beta3 integrins. Here we report that, whereas the conserved talin-integrin interaction is also required for beta1 activation, and talin F3 binds beta1 and beta3 integrins with comparable affinity, expression of the talin F3 domain is not sufficient to activate beta1 integrins. beta1 integrin activation could, however, be detected following expression of larger talin fragments that included the N-terminal and F1 domains, and mutagenesis indicates that these domains cooperate with talin F3 to mediate beta1 activation. This effect is not due to increased affinity for the integrin beta tail and we hypothesize that the N-terminal domains function by targeting or orienting talin in such a way as to optimize the interaction with the integrin tail. Analysis of beta3 integrin activation indicates that inclusion of the N-terminal and F1 domains also enhances F3-mediated beta3 activation. Our results therefore reveal a role for the N-terminal and F1 domains of talin during integrin activation and highlight differences in talin-mediated activation of beta1 and beta3 integrins. 相似文献
109.
Lad Y Jiang P Ruskamo S Harburger DS Ylänne J Campbell ID Calderwood DA 《The Journal of biological chemistry》2008,283(50):35154-35163
A link between sites of cell adhesion and the cytoskeleton is essential for regulation of cell shape, motility, and signaling. Migfilin is a recently identified adaptor protein that localizes at cell-cell and cell-extracellular matrix adhesion sites, where it is thought to provide a link to the cytoskeleton by interacting with the actin cross-linking protein filamin. Here we have used x-ray crystallography, NMR spectroscopy, and protein-protein interaction studies to investigate the molecular basis of migfilin binding to filamin. We report that the N-terminal portion of migfilin can bind all three human filamins (FLNa, -b, or -c) and that there are multiple migfilin-binding sites in FLNa. Human filamins are composed of an N-terminal actin-binding domain followed by 24 immunoglobulin-like (IgFLN) domains and we find that migfilin binds preferentially to IgFLNa21 and more weakly to IgFLNa19 and -22. The filamin-binding site in migfilin is localized between Pro(5) and Pro(19) and binds to the CD face of the IgFLNa21 beta-sandwich. This interaction is similar to the previously characterized beta 7 integrin-IgFLNa21 interaction and migfilin and integrin beta tails can compete with one another for binding to IgFLNa21. This suggests that competition between filamin ligands for common binding sites on IgFLN domains may provide a general means of modulating filamin interactions and signaling. In this specific case, displacement of integrin tails from filamin by migfilin may provide a mechanism for switching between different integrin-cytoskeleton linkages. 相似文献
110.