2014
DOI: 10.1208/s12248-014-9627-2
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Effects of Replacement of Factor VIII Amino Acids Asp519 and Glu665 with Val on Plasma Survival and Efficacy In Vivo

Abstract: Proteolytic cleavage of factor VIII (FVIII) to activated FVIIIa is required for participation in the coagulation cascade. The A2 domain is no longer covalently bound in the resulting activated heterotrimer and is highly unstable. Aspartic acid (D) 519 and glutamic acid (E) 665 at the A1-A2 and A2-A3 domain interfaces were identified as acidic residues in local hydrophobic pockets. Replacement with hydrophobic valine (V; D519V/E665V) improved the stability and activity of the mutant FVIII over the wild-type (WT… Show more

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“…The folding of selected preparations of the WT and CO was assessed by far‐UV CD in comparison with a BDD‐FVIII control. Figure (A) shows an overlay of the normalized spectra; each of these exhibited a strong negative extremum at 219 nm, typical for the β‐structure‐rich proteins and reported for FVIII . The estimated percentage of the β‐structures, including β‐sheet and β‐turn elements, was similar between the samples (Fig.…”
Section: Resultsmentioning
confidence: 65%
“…The folding of selected preparations of the WT and CO was assessed by far‐UV CD in comparison with a BDD‐FVIII control. Figure (A) shows an overlay of the normalized spectra; each of these exhibited a strong negative extremum at 219 nm, typical for the β‐structure‐rich proteins and reported for FVIII . The estimated percentage of the β‐structures, including β‐sheet and β‐turn elements, was similar between the samples (Fig.…”
Section: Resultsmentioning
confidence: 65%