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排序方式: 共有287条查询结果,搜索用时 31 毫秒
81.
82.
Zhuang Z Jewett AI Kuttimalai S Bellesia G Gnanakaran S Shea JE 《Biophysical journal》2011,(5):1306-1315
Natively disordered proteins belong to a unique class of biomolecules whose function is related to their flexibility and their ability to adopt desired conformations upon binding to substrates. In some cases these proteins can bind multiple partners, which can lead to distinct structures and promiscuity in functions. In other words, the capacity to recognize molecular patterns on the substrate is often essential for the folding and function of intrinsically disordered proteins. Biomolecular pattern recognition is extremely relevant both in vivo (e.g., for oligomerization, immune response, induced folding, substrate binding, and molecular switches) and in vitro (e.g., for biosensing, catalysis, chromatography, and implantation). Here, we use a minimalist computational model system to investigate how polar/nonpolar patterns on a surface can induce the folding of an otherwise unstructured peptide. We show that a model peptide that exists in the bulk as a molten globular state consisting of many interconverting structures can fold into either a helix-coil-helix or an extended helix structure in the presence of a complementary designed patterned surface at low hydrophobicity (3.7%) or a uniform surface at high hydrophobicity (50%). However, we find that a carefully chosen surface pattern can bind to and catalyze the folding of a natively unfolded protein much more readily or effectively than a surface with a noncomplementary or uniform distribution of hydrophobic residues. 相似文献
83.
84.
Bellesia G Jewett AI Shea JE 《Protein science : a publication of the Protein Society》2011,20(5):818-826
We use a recently developed coarse-grained computational model to investigate the relative stability of two different sets of de novo designed four-helix bundle proteins. Our simulations suggest a possible explanation for the experimentally observed increase in stability of the four-helix bundles with increasing sequence length. In details, we show that both short subsequences composed only by polar residues and additional nonpolar residues inserted, via different point mutations in ad hoc positions, seem to play a significant role in stabilizing the four-helix bundle conformation in the longer sequences. Finally, we propose an additional mutation that rescues a short amino acid sequence that would otherwise adopt a compact misfolded state. Our work suggests that simple computational models can be used as a complementary tool in the design process of de novo proteins. 相似文献
85.
Vorup-Jensen T Chi L Gjelstrup LC Jensen UB Jewett CA Xie C Shimaoka M Linhardt RJ Springer TA 《The Journal of biological chemistry》2007,282(42):30869-30877
The interactions between cell surface receptors and sulfated glucosamineglycans serve ubiquitous roles in cell adhesion and receptor signaling. Heparin, a highly sulfated polymer of uronic acids and glucosamine, binds strongly to the integrin receptor alphaXbeta2 (p150,95, CD11c/CD18). Here, we analyze the structural motifs within heparin that constitute high affinity binding sites for the I domain of integrin alphaXbeta2. Heparin oligomers with chain lengths of 10 saccharide residues or higher provide strong inhibition of the binding by the alphaX I domain to the complement fragment iC3b. By contrast, smaller oligomers or the synthetic heparinoid fondaparinux were not able to block the binding. Semipurified heparin oligomers with 12 saccharide residues identified the fully sulfated species as the most potent antagonist of iC3b, with a 1.3 microM affinity for the alphaX I domain. In studies of direct binding by the alphaX I domain to immobilized heparin, we found that the interaction is conformationally regulated and requires Mg2+. Furthermore, the fully sulfated heparin fragment induced conformational change in the ectodomain of the alphaXbeta2 receptor, also demonstrating allosteric linkage between heparin binding and integrin conformation. 相似文献
86.
The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi 总被引:3,自引:2,他引:1
Jewett MW Lawrence K Bestor AC Tilly K Grimm D Shaw P VanRaden M Gherardini F Rosa PA 《Molecular microbiology》2007,64(5):1358-1374
Borrelia burgdorferi, the aetiological agent of Lyme disease, follows a life cycle that involves passage between the tick vector and the mammalian host. To investigate the role of the 36 kb linear plasmid, lp36 (also designated the B. burgdorferi K plasmid), in the infectious cycle of B. burgdorferi, we examined a clone lacking this plasmid, but containing all other plasmids known to be required for infectivity. Our results indicated that lp36 was not required for spirochete survival in the tick, but the clone lacking lp36 demonstrated low infectivity in the mammal. Restoration of lp36 to the mutant strain confirmed that the infectivity defect was due to loss of lp36. Moreover, spirochetes lacking lp36 exhibited a nearly 4-log increase in ID(50) relative to the isogenic lp36(+) clone. The infectivity defect of lp36-minus spirochetes was localized, in part, to loss of the bbk17 (adeC) gene, which encodes an adenine deaminase. This work establishes a vital role for lp36 in the infectious cycle of B. burgdorferi and identifies the bbk17 gene as a component of this plasmid that contributes to mammalian infectivity. 相似文献
87.
Jewett MW Byram R Bestor A Tilly K Lawrence K Burtnick MN Gherardini F Rosa PA 《Molecular microbiology》2007,66(4):975-990
The genome of Borrelia burgdorferi is composed of one linear chromosome and approximately 20 linear and circular plasmids. Although some plasmids are required by B. burgdorferi in vivo, most plasmids are dispensable for growth in vitro. However, circular plasmid (cp) 26 is present in all natural isolates and has never been lost during in vitro growth. This plasmid carries ospC, which is critical for mammalian infection. We previously showed that cp26 encodes essential functions, including the telomere resolvase, ResT, and hence cannot be displaced. Here we identify two additional essential genes on cp26, bbb26 and bbb27, through a systematic attempt to inactivate each open reading frame (ORF). Furthermore, an incompatible plasmid carrying resT, bbb26 and bbb27 could displace cp26. Computational and experimental analyses suggested that both BBB26 and BBB27 are membrane-associated, periplasmic proteins. These data indicate that bbb26 and bbb27 encode essential but possibly redundant functions and that one or the other of these cp26 genes, in addition to resT, is required for bacterial viability. We conclude that the genetic linkage of critical physiological and virulence functions on cp26 is pertinent to its stable maintenance throughout the evolution of B. burgdorferi. 相似文献
88.
Sil Park Keiichi Kanayama Kawaljit Kaur Han-Ching Helen Tseng Sina Banankhah Davood Talebi Quje James W. Sayre Anahid Jewett Ichiro Nishimura 《The Journal of biological chemistry》2015,290(28):17349-17366
Osteonecrosis of the jaw (ONJ), an uncommon co-morbidity in patients treated with bisphosphonates (BP), occurs in the segment of jawbone interfacing oral mucosa. This study aimed to investigate a role of oral mucosal barrier γδ T cells in the pathogenesis of ONJ. Female C57Bl/6J (B6) mice received a bolus zoledronate intravenous injection (ZOL, 540 μg/kg), and their maxillary left first molars were extracted 1 week later. ZOL-treated mice (WT ZOL) delayed oral wound healing with patent open wounds 4 weeks after tooth extraction with characteristic oral epithelial hyperplasia. γδ T cells appeared within the tooth extraction site and hyperplastic epithelium in WT ZOL mice. In ZOL-treated γδ T cell null (Tcrd−/− ZOL) mice, the tooth extraction open wound progressively closed; however, histological ONJ-like lesions were identified in 75 and 60% of WT ZOL and Tcrd−/− ZOL mice, respectively. Although the bone exposure phenotype of ONJ was predominantly observed in WT ZOL mice, Tcrd−/− ZOL mice developed the pustule/fistula disease phenotype. We further addressed the role of γδ T cells from human peripheral blood (h-γδ T cells). When co-cultured with ZOL-pretreated human osteoclasts in vitro, h-γδ T cells exhibited rapid expansion and robust IFN-γ secretion. When h-γδ T cells were injected into ZOL-treated immunodeficient (Rag2−/− ZOL) mice, the oral epithelial hyperplasia developed. However, Rag2−/− ZOL mice did not develop osteonecrosis. The results indicate that γδ T cells are unlikely to influence the core osteonecrosis mechanism; however, they may serve as a critical modifier contributing to the different oral mucosal disease variations of ONJ. 相似文献
89.
Lina Basel-Vanagaite Rüstem Yilmaz Sha Tang Miriam S. Reuter Nils Rahner Dorothy K. Grange Megan Mortenson Patrick Koty Heather Feenstra Kelly D. Farwell Gonzalez Heinrich Sticht Nathalie Boddaert Julie Désir Kwame Anyane-Yeboa Christiane Zweier André Reis Christian Kubisch Tamison Jewett Wenqi Zeng Guntram Borck 《Human genetics》2014,133(7):939-949
Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis–ptosis–intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello–Carey syndrome as well as the patient reported to have a “new” syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello–Carey syndrome, and suggest the single designation “Kaufman oculocerebrofacial syndrome”. 相似文献
90.
Craig A. Gedye Ali Hussain Joshua Paterson Alannah Smrke Harleen Saini Danylo Sirskyj Keira Pereira Nazleen Lobo Jocelyn Stewart Christopher Go Jenny Ho Mauricio Medrano Elzbieta Hyatt Julie Yuan Stevan Lauriault Maria Kondratyev Twan van den Beucken Michael Jewett Peter Dirks Cynthia J. Guidos Jayne Danska Jean Wang Bradly Wouters Benjamin Neel Robert Rottapel Laurie E. Ailles 《PloS one》2014,9(8)
Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC) platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell markers. 相似文献