排序方式: 共有71条查询结果,搜索用时 15 毫秒
11.
Qahwash I He W Tomasselli A Kletzien RF Yan R 《The Journal of biological chemistry》2004,279(37):39010-39016
Membrane-bound BACE1 naturally cleaves its transmembrane substrate amyloid precursor protein (APP) at the two adjacent beta- and beta'-sites. Cleavage at these two sites generates the heterogeneous N-terminal end of APP C-terminal fragments that are further processed by gamma-secretase to release Abeta-(1-40/42) or Abeta-(11-40/42). The significance underlying Abeta-(11-40/42) in Alzheimer's disease pathogenesis has remained to be experimentally elucidated, but increased production of Abeta-(1-40/42) has been broadly demonstrated to contribute to amyloid depositions in senile plaques. In this study, we show that the cleavage of APP at the beta-site by BACE1 is readily disrupted through limited structural twists, whereas the beta'-site is relatively better positioned to gain access to the BACE1 catalytic cavity. Radical insertion or deletion of residues between beta- and beta'-site also favors cleavage of APP at the beta'-site. On the other hand, either lengthening or shortening the loop region of BACE1 has a minor impact on the selective cleavage of APP at these two adjacent sites, but significantly shortening the loop region impairs the ability of BACE1 to process APP at both sites. Thus, processing of APP by BACE1 is clearly dependent on a mutual structural compatibility in addition to the sequence feature. The knowledge gained from this study will potentially offer an opportunity for rational design of small molecule drugs to block the cleavage of APP specifically at the beta-site while not disturbing the functions of other cellular aspartyl proteases. 相似文献
12.
13.
14.
15.
Qahwash IM Boire A Lanning J Krausz T Pytel P Meredith SC 《The Journal of biological chemistry》2007,282(51):36987-36997
Beta-amyloid (Abeta) aggregates at low concentrations in vivo, and this may involve covalently modified forms of these peptides. Modification of Abeta by 4-hydroxynonenal (4-HNE) initially increases the hydrophobicity of these peptides and subsequently leads to additional reactions, such as peptide cross-linking. To model these initial events, without confounding effects of subsequent reactions, we modified Abeta at each of its amino groups using a chemically simpler, close analogue of 4-HNE, the octanoyl group: K16-octanoic acid (OA)-Abeta, K28-OA-Abeta, and Nalpha-OA-Abeta. Octanoylation of these sites on Abeta-(1-40) had strikingly different effects on fibril formation. K16-OA-Abeta and K28-OA-Abeta, but not Nalpha-OA-Abeta, had increased propensity to aggregate. The type of aggregate (electron microscopic appearance) differed with the site of modification. The ability of octanoyl-Abeta peptides to cross-seed solutions of Abeta was the inverse of their ability to form fibrils on their own (i.e. Abeta approximately Nalpha-OA-Abeta>K16-OA-Abeta>K28-OA-Abeta). By CD spectroscopy, K16-OA-Abeta and K28-OA-Abeta had increased beta-sheet propensity compared with Abeta-(1-40) or Nalpha-OA-Abeta. K16-OA-Abeta and K28-OA-Abeta were more amphiphilic than Abeta-(1-40) or Nalpha-OA-Abeta, as shown by lower "critical micelle concentrations" and higher monolayer collapse pressures. Finally, K16-OA-Abeta and K28-OA-Abeta are much more cytotoxic to N2A cells than Abeta-(1-40) or Nalpha-OA-Abeta. The greater cytotoxicity of K16-OA-Abeta and K28-OA-Abeta may reflect their greater amphiphilicity. We conclude that lipidation can make Abeta more prone to aggregation and more cytotoxic, but these effects are highly site-specific. 相似文献
16.
17.
18.
Testicular immune privilege promotes transplantation tolerance by altering the balance between memory and regulatory T cells 总被引:10,自引:0,他引:10
Nasr IW Wang Y Gao G Deng S Diggs L Rothstein DM Tellides G Lakkis FG Dai Z 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(10):6161-6168
Immune responses are suppressed in immunologically privileged sites, which may provide a unique opportunity to prolong allograft survival. However, it is unknown whether testicular immune privilege promotes transplantation tolerance. Mechanisms underlying immune privilege are also not well understood. Here we found that islet transplantation in the testis, an immunologically privileged site, generates much less memory CD8(+) T cells but induces more Ag-specific CD4(+)CD25(+) regulatory T cells than in a conventional site. These CD4(+)CD25(+) cells exhibited the suppression of alloimmune responses in vivo and in vitro. Despite the immune regulation, intratesticular islet allografts all were rejected within 42 days after transplantation although they survived longer than renal subcapsular islet allografts. However, blocking CD40/CD40L costimulation induced the tolerance of intratesticular, but not renal subcapsular, islet allografts. Tolerance to intratesticular islet allografts spread to skin allografts in the non-privileged sites. Either transfer of memory CD8(+) T cells or deletion of CD25(+) T cells in vivo broke islet allograft tolerance. Thus, transplantation tolerance requires both costimulatory blockade, which suppresses acute allograft rejection, and a favorable balance between memory and regulatory T cells that could favorably prevent late allograft failure. These findings reveal novel mechanisms of immune privilege and provide direct evidence that testicular immune privilege fosters the induction of transplantation tolerance to allografts in both immunologically privileged and non-privileged sites. 相似文献
19.
20.
Marin Concepció Fuentes Mireya Alobid Isam Tubita Valeria Rojas-Lechuga María Jesús Mullol Joaquim 《Neurochemical research》2022,47(4):1025-1036
Neurochemical Research - There is increasing preclinical and clinical data supporting a potential association between Traumatic Brain Injury (TBI) and Parkinson’s disease (PD). It has been... 相似文献