کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10537541 | 962777 | 2014 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The role of surface electrostatics on the stability, function and regulation of human cystathionine β-synthase, a complex multidomain and oligomeric protein
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کلمات کلیدی
Surface electrostaticsHEPESHCBSHomocysteine metabolismSAMITCHCUDSC4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid - 4- (2-Hydroxyethyl) piperazine-1-ethanesulfonic acidS-adenosyl-methionine - S-آدنوزیل-متیونینAllostery - آلوستریConformational disease - بیماری سازگاریRegulatory domain - دامنه نظارتیCatalytic domain - دامنه کاتالیستیLigand binding - لیگاند اتصالclassical homocystinuria - هموسیستینوری کلاسیکIsothermal titration calorimetry - کالری سنجی تیتاسیون ایزوترمالDifferential scanning calorimetry - کالریمتری روبشی افتراقی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آنالیزی یا شیمی تجزیه
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Human cystathionine β-synthase (hCBS) is a key enzyme of sulfur amino acid metabolism, controlling the commitment of homocysteine to the transsulfuration pathway and antioxidant defense. Mutations in hCBS cause inherited homocystinuria (HCU), a rare inborn error of metabolism characterized by accumulation of toxic homocysteine in blood and urine. hCBS is a complex multidomain and oligomeric protein whose activity and stability are independently regulated by the binding of S-adenosyl-methionine (SAM) to two different types of sites at its C-terminal regulatory domain. Here we study the role of surface electrostatics on the complex regulation and stability of hCBS using biophysical and biochemical procedures. We show that the kinetic stability of the catalytic and regulatory domains is significantly affected by the modulation of surface electrostatics through noticeable structural and energetic changes along their denaturation pathways. We also show that surface electrostatics strongly affect SAM binding properties to those sites responsible for either enzyme activation or kinetic stabilization. Our results provide new insight into the regulation of hCBS activity and stability in vivo with implications for understanding HCU as a conformational disease. We also lend experimental support to the role of electrostatic interactions in the recently proposed binding modes of SAM leading to hCBS activation and kinetic stabilization.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics - Volume 1844, Issue 9, September 2014, Pages 1453-1462
Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics - Volume 1844, Issue 9, September 2014, Pages 1453-1462
نویسندگان
Angel L. Pey, Tomas Majtan, Jan P. Kraus,