Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2334-9. Epub 2001 Feb 20.

Destabilization of Ca2+-free gelsolin may not be responsible for proteolysis in Familial Amyloidosis of Finnish Type.

Author information

1
Department of Chemistry and the Skaggs Institute of Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road (MB12), La Jolla, CA 92037, USA.

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.

PMID:
11226240
PMCID:
PMC30139
DOI:
10.1073/pnas.041452598
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center