Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context.

نویسندگان

  • A J McGettrick
  • V Knott
  • A Willis
  • P A Handford
چکیده

Mutations in the human fibrillin-1 (FBN-1) gene cause Marfan syndrome (MFS), an autosomal dominant disease of connective tissue. Fibrillin-1, a 350 kDa extracellular calcium binding protein, is a major structural component of 10-12 nm microfibrils and consists predominantly of two repeated module types: the calcium binding epidermal growth factor-like (cbEGF) domain and the transforming growth factor beta1 binding protein-like (TB) domain. A group of reported FBN-1 mutations is predicted to reduce calcium binding to cbEGF domains by removal of a side chain ligand for calcium. These mutations occur in two protein domain contexts, either in a cbEGF preceded by a TB domain or in a cbEGF preceded by another cbEGF domain. In this study we have used three proteases to probe structural changes caused by an N2144S MFS calcium binding mutation in a TB6-cbEGF32 and a cbEGF32-33 domain pair, and an N2183S mutation in the cbEGF32-33 pair. N-terminal sequence analysis of domain pairs digested in the presence and absence of calcium show that: (i) domain interactions between TB6 and cbEGF32 are calcium independent, despite the presence of a calcium binding site in cbEGF32; (ii) domain interactions between cbEGF32 and cbEGF33 are calcium dependent; and (iii) an N-->S mutation causes increased proteolytic susceptibility only when located in cbEGF33, consistent with a key role for interdomain calcium binding in rigidifying cbEGF domain linkages. These data demonstrate for the first time that the structural consequences of calcium binding mutations in fibrillin-1 cbEGF domains can be influenced by domain context.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Cellular and molecular studies of Marfan syndrome mutations identify co-operative protein folding in the cbEGF12-13 region of fibrillin-1.

Human fibrillin-1 is an extra-cellular matrix glycoprotein with a modular organisation that includes 43 calcium-binding epidermal growth factor-like (cbEGF) domains arranged as multiple tandem repeats interspersed with transforming growth factor beta binding protein-like (TB) domains. We have studied Marfan syndrome-causing mutations which affect calcium binding to cbEGF13, and demonstrate that...

متن کامل

Informative STR Markers for Marfan Syndrome in Birjand, Iran

Objective(s)Marfan syndrome (MFS) is a severe connective tissue disorder withan autosomal dominant inheritance pattern. Early diagnosis is critical in MFS. Because of the large size of fibrillin-1 gene (FBN1), the uniqueness of mutations, and the absence of genotype-to-phenotype correlations linkage analysis can be very helpful for early diagnosis of MFS. In this study, eight polymorphic marker...

متن کامل

Solution Structure of a Pair of Calcium-Binding Epidermal Growth Factor-like Domains: Implications for the Marfan Syndrome and Other Genetic Disorders

The nuclear magnetic resonance structure of a covalently linked pair of calcium-binding (cb) epidermal growth factor-like (EGF) domains from human fibrillin-1, the protein defective in the Marfan syndrome, is described. The two domains are in a rigid, rod-like arrangement, stabilized by interdomain calcium binding and hydrophobic interactions. We propose a model for the arrangement of fibrillin...

متن کامل

Comparative Investigation of R213G Mutation in DNA-Binding Domain of P53 Protein via Molecular Dynamics Simulation

Introduction: P53 is a tumor suppressor protein with numerous missense mutations identified in its gene. These mutations are observed in a vast number of cancers. R213G is one of them which has a role in metastatic lung cancers. In this research, R213G was studied in comparison with the wild type via molecular dynamics simulation. Method: For the three-dimensional structure of the wild-type P53...

متن کامل

Twelve novel FBN1 mutations in Marfan syndrome and Marfan related phenotypes test the feasibility of FBN1 mutation testing in clinical practice.

Marfan syndrome (MFS) is one of the major heritable disorders of connective tissue with a prevalence of between 1 in 5-10 000. 2 It is characterised by features in the cardiovascular, ocular, and musculoskeletal systems and the Ghent criteria form a useful framework for its diagnosis. Mutations in FBN1 encoding the extracellular matrix protein fibrillin-1 classically cause MFS. Fibrillin-1, com...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Human molecular genetics

دوره 9 13  شماره 

صفحات  -

تاریخ انتشار 2000