Title | The 8 and 5 kDa fragments of plasma gelsolin form amyloid fibrils by a nucleated polymerization mechanism, while the 68 kDa fragment is not amyloidogenic. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Solomon JP, Yonemoto IT, Murray AN, Price JL, Powers ET, Balch WE, Kelly JW |
Journal | Biochemistry |
Volume | 48 |
Issue | 48 |
Pagination | 11370-80 |
Date Published | 2009 Dec 08 |
ISSN | 1520-4995 |
Keywords | Amyloid, Amyloidosis, Electrophoresis, Polyacrylamide Gel, Gelsolin, Humans, Microscopy, Atomic Force, Molecular Weight, Peptide Fragments, Spectrometry, Fluorescence |
Abstract | Familial amyloidosis of Finnish type (FAF), or gelsolin amyloidosis, is a systemic amyloid disease caused by a mutation (D187N/Y) in domain 2 of human plasma gelsolin, resulting in domain 2 misfolding within the secretory pathway. When D187N/Y gelsolin passes through the Golgi, furin endoproteolysis within domain 2 occurs as a consequence of the abnormal conformations that enable furin to bind and cleave, resulting in the secretion of a 68 kDa C-terminal fragment (amino acids 173-755, C68). The C68 fragment is cleaved upon secretion from the cell by membrane type 1 matrix metalloprotease (MT1-MMP), affording the 8 and 5 kDa fragments (amino acids 173-242 and 173-225, respectively) comprising the amyloid fibrils in FAF patients. Herein, we show that the 8 and 5 kDa gelsolin fragments form amyloid fibrils by a nucleated polymerization mechanism. In addition to demonstrating the expected concentration dependence of a nucleated polymerization reaction, the addition of preformed amyloid fibrils, or "seeds", was shown to bypass the requirement for the formation of a high-energy nucleus, accelerating 8 and 5 kDa D187N gelsolin amyloidogenesis. The C68 fragment can form small oligomers, but not amyloid fibrils, even when seeded with preformed 8 kDa fragment plasma gelsolin fibrils. Because the 68 kDa fragment of gelsolin does not form amyloid fibrils in vitro or in a recently published transgenic mouse model of FAF, we propose that administration of an MT1-MMP inhibitor could be an effective strategy for the treatment of FAF. |
DOI | 10.1021/bi901368e |
Alternate Journal | Biochemistry |
PubMed ID | 19904968 |
Grant List | AG018917 / AG / NIA NIH HHS / United States |
Related Faculty:
James Solomon, M.D., Ph.D.