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Colin W. Garvie Keshav Vasanthavada Qing Xiang 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(8):1562-1571
RNase L is part of the innate immune response to viral infection. It is activated by a small oligonucleotide (2–5A) whose synthesis is initiated as part of the interferon response. Binding of 2–5A to the N-terminal regulatory region, the ANK domain, of RNase L activates its ribonuclease activity and results in cleavage of RNA in the cell, which ultimately leads to apoptosis of the infected cell. The mechanism by which 2–5A activates the ribonuclease activity of RNase L is currently unclear but 2–5A has been shown to induce dimerization of RNase L. To investigate the importance of dimerization of RNase L, we developed a 15 kDa dimerization-inducing protein domain that was fused to the N-terminus of RNase L. From these studies we provide direct evidence that dimerization of RNase L occurs at physiologically relevant protein concentrations and correlates with activation of ribonuclease activity. We also show that the binding of 2–5A to RNase L promotes dimerization of the ANK domain and suggest how this could transmit a signal to the rest of the protein to activate ribonuclease activity. Finally, we show that the dimerization-inducing domain can be used as a general fusion partner to aid in protein expression and purification. 相似文献
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Point mutations at the catalytic site of PCSK9 inhibit folding,autoprocessing, and interaction with the LDL receptor 下载免费PDF全文
Colin W. Garvie Cara V. Fraley Nadine H. Elowe Elizabeth K. Culyba Christopher T. Lemke Brian K. Hubbard Virendar K. Kaushik Douglas S. Daniels 《Protein science : a publication of the Protein Society》2016,25(11):2018-2027
Circulating low‐density lipoprotein cholesterol (LDLc) is regulated by membrane‐bound LDL receptor (LDLr). Upon LDLc and LDLr interaction the complex is internalized by the cell, leading to LDLc degradation and LDLr recycling back to the cell surface. The proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates this cycling. PCSK9 is secreted from the cell and binds LDLr. When the complex is internalized, PCSK9 prevents LDLr from shuttling back to the surface and instead targets it for degradation. PCSK9 is a serine protease expressed as a zymogen that undergoes autoproteolysis, though the two resulting protein domains remain stably associated as a heterodimer. This PCSK9 autoprocessing is required for the protein to be secreted from the cell. To date, direct analysis of PCSK9 autoprocessing has proven challenging, as no catalytically active zymogen has been isolated. A PCSK9 loss‐of‐function point mutation (Q152H) that reduces LDLc levels two‐fold was identified in a patient population. LDLc reduction was attributed to a lack of PCSK9(Q152H) autoprocessing preventing secretion of the protein. We have isolated a zymogen form of PCSK9, PCSK9(Q152H), and a related mutation (Q152N), that can undergo slow autoproteolysis. We show that the point mutation prevents the formation of the mature form of PCSK9 by hindering folding, reducing the rate of autoproteolysis, and destabilizing the heterodimeric form of the protein. In addition, we show that the zymogen form of PCSK9 adopts a structure that is distinct from the processed form and is unable to bind a mimetic peptide based on the EGF‐A domain of the LDLr. 相似文献
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Andrew Garvie 《BMJ (Clinical research ed.)》1919,2(3069):519-523
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Traditional metapopulation theory classifies a metapopulation as a spatially homogeneous population that persists on neighboring habitat patches. The fate of each population on a habitat patch is a function of a balance between births and deaths via establishment of new populations through migration to neighboring patches. In this study, we expand upon traditional metapopulation models by incorporating spatial heterogeneity into a previously studied two-patch nonlinear ordinary differential equation metapopulation model, in which the growth of a general prey species is logistic and growth of a general predator species displays a Holling type II functional response. The model described in this work assumes that migration by generalist predator and prey populations between habitat patches occurs via a migratory corridor. Thus, persistence of species is a function of local population dynamics and migration between spatially heterogeneous habitat patches. Numerical results generated by our model demonstrate that population densities exhibit periodic plane-wave phenomena, which appear to be functions of differences in migration rates between generalist predator and prey populations. We compare results generated from our model to results generated by similar, but less ecologically realistic work, and to observed population dynamics in natural metapopulations. 相似文献
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We present the analysis of two reaction-diffusion systems modelling predator-prey interactions, where the predator displays the Holling type II functional response, and in the absence of predators, the prey growth is logistic. The local analysis is based on the application of qualitative theory for ordinary differential equations and dynamical systems, while the global well-posedness depends on invariant sets and differential inequalities. The key result is an L (∞)-stability estimate, which depends on a polynomial growth condition for the kinetics. The existence of an a priori L ( p )-estimate, uniform in time, for all p≥1, implies L (∞)-uniform bounds, given any nonnegative L (∞)-initial data. The applicability of the L (∞)-estimate to general reaction-diffusion systems is discussed, and how the continuous results can be mimicked in the discrete case, leading to stability estimates for a Galerkin finite-element method with piecewise linear continuous basis functions. In order to verify the biological wave phenomena of solutions, numerical results are presented in two-space dimensions, which have interesting ecological implications as they demonstrate that solutions can be 'trapped' in an invariant region of phase space. 相似文献