Effect of metal cations on the conformation and inactivation of recombinant human factor VIII

Journal of Pharmaceutical Sciences
Tiffany S DerrickC Russell Middaugh

Abstract

Heavy metals have been implicated in the aggregation of proteins and the pathophysiology of several neurodegenerative diseases. Herein, we describe the interaction of recombinant human factor VIII (rhFVIII) with Al(+3), Tb(+3), Co(+2), and Fe(+3) using a combination of intrinsic fluorescence, circular dichroism, and high-resolution fourth-derivative absorbance analysis. rhFVIII in solution was titrated with the metal cations and the properties of the resulting complexes were examined. rhFVIII has a tendency to aggregate and inactivate slowly over time under physiological conditions, but this aggregation process is greatly accelerated in the presence of metals with Al(+3) being the most efficient. This leads to a complete loss of activity of the protein. Al(+3)-induced conformational changes in the protein were small but detectable with limited changes seen in secondary and tertiary structure. Because rhFVIII is a multidomain protein with subunits linked through divalent metal cations, the small intramolecular changes seen may be attributed to rearrangements of the subunits to an aggregation-competent conformer that is very similar to that of the native form.

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Citations

Feb 25, 2005·The Journal of Biological Chemistry·Vivek S PurohitSathyamangalam V Balasubramanian
Jun 27, 2006·The AAPS Journal·Vivek S Purohit, Sathyamangalam V Balasubramanian
Oct 3, 2007·The AAPS Journal·Razvan D MicleaSathy V Balu-Iyer
Jul 30, 2005·Journal of Pharmaceutical Sciences·Karthik RamaniSathyamangalam V Balasubramanian
Jan 12, 2008·Journal of Pharmaceutical Sciences·Tim J Kamerzell, C Russell Middaugh
Apr 29, 2005·Journal of Pharmaceutical Sciences·Karthik RamaniSathyamangalam V Balasubramanian
Nov 21, 2007·Journal of Pharmaceutical Sciences·Yatin R GokarnSusan Hershenson
May 31, 2012·Journal of Pharmaceutical Sciences·Ning LiWei Wang
Feb 10, 2009·Journal of Pharmaceutical Sciences·Maulik TrivediTeruna J Siahaan
Apr 26, 2012·International Journal of Pharmaceutics·Maulik TrivediTeruna J Siahaan
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