Abstract:
:Mutations at position 187 in secreted gelsolin enable aberrant proteolysis at the 172-173 and 243-244 amide bonds, affording the 71-residue amyloidogenic peptide deposited in Familial Amyloidosis of Finnish Type (FAF). Thermodynamic comparisons of two different domain 2 constructs were carried out to study possible effects of the mutations on proteolytic susceptibility. In the construct we consider to be most representative of domain 2 in the context of the full-length protein (134-266), the D187N FAF variant is slightly destabilized relative to wild type (WT) under the conditions of urea denaturation, but exhibits a T(m) identical to WT. The D187Y variant is less stable to intermediate urea concentrations and exhibits a T(m) that is estimated to be approximately 5 degrees C lower than WT (pH 7.4, Ca(2+)-free). Although the thermodynamic data indicate that the FAF mutations may slightly destabilize domain 2, these changes are probably not sufficient to shift the native to denatured state equilibrium enough to enable the proteolysis leading to FAF. Biophysical data indicate that these two FAF variants may have different native state structures and possibly different pathways of amyloidosis.
journal_name
Proc Natl Acad Sci U S Aauthors
Ratnaswamy G,Huff ME,Su AI,Rion S,Kelly JWdoi
10.1073/pnas.041452598keywords:
subject
Has Abstractpub_date
2001-02-27 00:00:00pages
2334-9issue
5eissn
0027-8424issn
1091-6490pii
041452598journal_volume
98pub_type
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