کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10956108 | 1098784 | 2014 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation
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کلمات کلیدی
GCKpost nuclear supernatantα-d-glucoseRRLGKRPhGKDulbecco’s modified eagles mediumIFGHEKDMEMPDBGlcBCAImpaired fasting glucose - اختلال قندخون ناشتاbicinchoninic acid - بیسینکنینیک اسیدAggregation - تجمعMin - حداقلSelf-association - خودآموزیMaturity-onset diabetes of the young - دیابت مبتلا به بلوغ زودرسrabbit reticulocyte lysate - رتیکولوسیت لوزی خرگوشProtein misfolding - غلظت پروتئینCatalytic activity - فعالیت کاتالیستیMODY - مدProtein Data Bank - پروتئین بانک اطلاعاتیGlucokinase regulatory protein - پروتئین تنظیم کننده گلوکوکینازPNS - کارمندان دولتhuman embryonic kidney - کلیه جنین انسان
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation](/preview/png/10956108.png)
چکیده انگلیسی
GCK-MODY, dominantly inherited mild hyperglycemia, is associated with more than 600 mutations in the glucokinase gene. Different molecular mechanisms have been shown to explain GCK-MODY. Here, we report a Pakistani family harboring the glucokinase mutation c.823C > T (p.R275C). The recombinant and in cellulo expressed mutant pancreatic enzyme revealed slightly increased enzyme activity (kcat) and normal affinity for α-D-glucose, and resistance to limited proteolysis by trypsin comparable with wild-type. When stably expressed in HEK293 cells and MIN6 β-cells (at different levels), the mutant protein appeared misfolded and unstable with a propensity to form dimers and aggregates. Its degradation rate was increased, involving the lysosomal and proteasomal quality control systems. On mutation, a hydrogen bond between the R275 side-chain and the carbonyl oxygen of D267 is broken, destabilizing the F260-L271 loop structure and the protein. This promotes the formation of dimers/aggregates and suggests that an increased cellular degradation is the molecular mechanism by which R275C causes GCK-MODY.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular and Cellular Endocrinology - Volume 382, Issue 1, 25 January 2014, Pages 55-65
Journal: Molecular and Cellular Endocrinology - Volume 382, Issue 1, 25 January 2014, Pages 55-65
نویسندگان
Maria Negahdar, Ingvild Aukrust, Janne Molnes, Marie H. Solheim, Bente B. Johansson, Jørn V. Sagen, Knut Dahl-Jørgensen, Rohit N. Kulkarni, Oddmund Søvik, Torgeir Flatmark, Pål R. Njølstad, Lise Bjørkhaug,