Accession Number:

ADA439264

Title:

Analysis of Keratin Filament Assembly/Disassembly and Structure Following Modification by Sulfur Mustard Analogs

Descriptive Note:

Final rept. 15 Jun 2002-14 Jun 2005

Corporate Author:

CALIFORNIA UNIV DAVIS

Report Date:

2005-07-01

Pagination or Media Count:

44.0

Abstract:

The modification of keratin and vimentin intermediate filaments and proteins by the sulfur mustard analogs chloroethyl ethyl sulfide and mechlorethamine has been studied using electron microscopic and electron paramagnetic approaches. The modification of intact filaments leads to abnormalities in the filaments such that native filament appearance is destroyed. Modification of purified proteins, followed by dialysis to assemble native filaments, shows that the modified proteins do not assemble into smooth native looking filaments. In both cases, the appearance in the electron microscope is filamentous, but with much more particulate, irregular aggregations. Comparison of these chemically modified proteins to specific mutations associated with skin blistering diseases reveals difference between the filaments. Using an electron paramagnetic approach, it has been possible to examine the early stages of normal heteropolymeric keratin filament assembly for characteristics that are related to our findings with the homopolymeric protein vimentin. Thus, we have identified spectral changes that occur during assembly and have further identified amino acid regions in one keratin protein that are in close proximity with another region of the polymerization partner. Subsequently, the assembly of chloroethyl ethyl sulfide and mechlorethamine treated keratins was analyzed, revealing a change in the assembly dynamics but showing evidence of some proper assembly. It is likely that near normal filament assembly occurs at early stages, but additional aberrant interactions are produced as a result of covalent modification.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research
  • Chemical, Biological and Radiological Warfare

Distribution Statement:

APPROVED FOR PUBLIC RELEASE