Effect of metal cations on the conformation and inactivation of recombinant human factor VIII
Effect of metal cations on the conformation and inactivation of recombinant human factor VIII
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DOI：
10.1002/jps.20167
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发表时间：
2004-10-01
影响因子：
3.8
通讯作者：
Middaugh, CR
中科院分区：
文献类型：
--
作者：
Derrick, TS;Kash, RS;Middaugh, CR
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. (C) 2004 Wiley-Liss, Inc.
