TY - JOUR
T1 - Amyloid properties of the leader peptide of variant B cystatin C
T2 - implications for Alzheimer and macular degeneration
AU - Sant'Anna, Ricardo
AU - Navarro, Susanna
AU - Ventura, Salvador
AU - Paraoan, Luminita
AU - Foguel, Debora
N1 - © 2016 Federation of European Biochemical Societies.
PY - 2016/3/7
Y1 - 2016/3/7
N2 - Variant B (VB) of cystatin C has a mutation in its signal peptide (A25T), which interferes with its processing leading to reduced secretion and partial retention in the vicinity of the mitochondria. There are genetic evidences of the association of VB with Alzheimer's disease (AD) and age-related macular degeneration (AMD). Here, we investigated aggregation and amyloid propensities of unprocessed VB combining computational and in vitro studies. Aggregation predictors revealed the presence of four aggregation-prone regions, with a strong one at the level of the signal peptide, which indeed formed toxic aggregates and mature amyloid fibrils in solution. In light of these results, we propose for the first time the role of the signal peptide in pathogenesis of AD and AMD.
AB - Variant B (VB) of cystatin C has a mutation in its signal peptide (A25T), which interferes with its processing leading to reduced secretion and partial retention in the vicinity of the mitochondria. There are genetic evidences of the association of VB with Alzheimer's disease (AD) and age-related macular degeneration (AMD). Here, we investigated aggregation and amyloid propensities of unprocessed VB combining computational and in vitro studies. Aggregation predictors revealed the presence of four aggregation-prone regions, with a strong one at the level of the signal peptide, which indeed formed toxic aggregates and mature amyloid fibrils in solution. In light of these results, we propose for the first time the role of the signal peptide in pathogenesis of AD and AMD.
KW - Alzheimer Disease/metabolism
KW - Amino Acid Sequence
KW - Amyloidogenic Proteins/chemistry
KW - Computational Biology
KW - Cystatin C/chemistry
KW - Humans
KW - Macular Degeneration/metabolism
KW - Molecular Sequence Data
KW - Protein Aggregates
KW - Protein Sorting Signals
KW - Protein Structure, Secondary
KW - Risk
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000371402700006&KeyUID=WOS:000371402700006
U2 - 10.1002/1873-3468.12093
DO - 10.1002/1873-3468.12093
M3 - Article (journal)
C2 - 26865059
SN - 0014-5793
VL - 590
SP - 644
EP - 654
JO - FEBS Letters
JF - FEBS Letters
IS - 5
ER -
