High-resolution NMR studies of fibrinogen-like peptides in solution: Structural basis for the bleeding disorder caused by a single mutation of Gly(12) to Val(12) in the A. alpha. chain of human fibrinogen Rouen
- Cornell Univ., Ithaca, NY (USA)
In human fibrinogen Rouen, which is the origin of a bleeding disorder, a single amino acid is mutated from Gly(12) to Val(12) in the A{alpha} Chain. In the previous paper of this series, this mutation was predicted to disrupt the structure of fibrinogen-like peptides bound to bovine thrombin. The structural basis of this bleeding disorder has been further assessed by studying the interaction of the following Val(12)-substituted human fibrinogen-like peptides with bovine thrombin in aqueous solution by use of two-dimensional NMR spectroscopy (including TRNOE): Ala-Asp-Ser-Gly-Glu-Gly-Asp(7)-Phe-Leu-Ala-Glu-Val(12)-Gly-Gly-Val-Arg(16)-Gly(17)-Pro-Arg-Val(Acm)-NH{sub 2} (F17), Ala-Asp-Ser-Gly-Glu-Cys(Acm)-Asp(7)-Phe-Leu-Ala-Glu-Val(12)-Gly-Gly-Val-Arg(16) (tF17). Binding of thrombin to peptides F16 and F17, and hence to tF16 and tF17 as a result of the cleavage of the Arg(16)-Gly(17) peptide bond, broadens the proton resonances of residues Asp(7) to Arg(16), suggesting that thrombin interacts specifically with this sequence of residues. Medium- and long-range TRNOE's were observed between the NH proton of Asp(7) and the C{sup {beta}}H protons of Ala(10) and between the ring protons of Phe(8) and the C{sup {gamma}}H protons of Val(12) and Val(15) in complexes of thrombin with both tF16 and tF17. A strong TRNOE, in peptides tF16 and tF17, between the C{sup beta}H protons of Glu(11) and the backbone NH proton of Val(12) was also observed. Thus, the bleeding disorder caused by the single mutation of Gly(12) to Val(12) may be due to the structural alteration of human fibrinogen Rouen identified here.
- OSTI ID:
- 5546053
- Journal Information:
- Biochemistry; (USA), Journal Name: Biochemistry; (USA) Vol. 28:7; ISSN 0006-2960; ISSN BICHA
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
62 RADIOLOGY AND NUCLEAR MEDICINE
AMINO ACID SEQUENCE
AMINO ACIDS
ANIMALS
AQUEOUS SOLUTIONS
BARYONS
BLOOD COAGULATION
CARBOXYLIC ACIDS
CATTLE
COAGULANTS
DISEASES
DISPERSIONS
DOMESTIC ANIMALS
DRUGS
ELEMENTARY PARTICLES
ENZYMES
FERMIONS
GLYCINE
HADRONS
HEMATOLOGIC AGENTS
HEMORRHAGE
HEMOSTATICS
HEREDITARY DISEASES
HYDROLASES
MAGNETIC RESONANCE
MAMMALS
MIXTURES
MOLECULAR STRUCTURE
MUTATIONS
NUCLEAR MAGNETIC RESONANCE
NUCLEONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
OVERHAUSER EFFECT
PATHOLOGICAL CHANGES
PEPTIDE HYDROLASES
PEPTIDES
PROTEINS
PROTONS
RESONANCE
RUMINANTS
SERINE PROTEINASES
SOLUTIONS
SYMPTOMS
THROMBIN
VALINE
VASCULAR DISEASES
VERTEBRATES