Characterization of the Amyloidogenic Peptides Amylin and PAP248-286.

Amyloid;Type II Diabetes;IAPP;HIV Transmission;SEVI;Biological Chemistry;Chemistry;Science;Chemistry

Hartman, KevinLim, Mi Hee ;

University of Michigan

关键词: Amyloid;    Type II Diabetes;    IAPP;    HIV Transmission;    SEVI;    Biological Chemistry;    Chemistry;    Science;    Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/91541/khartma_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Many diseases in the aging population are associated with a class of peptide that aggregates to form amyloidogenic fibers through a misfolding from random coil, to cross β-sheet fibrils. Diseases such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and transmission of viral infection are shown to be linked to different amyloidogenic peptides. In two different projects within the amyloid field, we have chosen to study or amylin, in relation to type II diabetes, as well as a fragment of prostatic acid phosphatase (PAP248-286) whose fibrils have been termed a semen-derived enhancer of viral infection (SEVI). In relation to the amylin peptide, different aspects of the physiological storage conditions were probed. High concentrations of the peptide have proven very disruptiveto membranes and very prone to aggregation in vitro, however in the secretory granule it is stored in mM concentrations. The three unique conditions to the granule are the relatively low pH (~6.0) and very high zinc (~14mM) and insulin (~4x amylin) concentrations. Here it is seen that separately, all three of these variables cause decreased membrane disruptive ability of amylin, and decreased ability to aggregate into amyloid fibers. Disruption of this environment such as lowered zinc concentrations could facilitate amylin’s membrane disruptive ability and further the progression of type II diabetes. We also characterized the relatively unstudied PAP248-286 peptide also an amyloid, and its interaction with model membrane systems to show that the peptide itself causes lipid aggregation and induces vesicle fusion, as would be the case for a peptide which facilitates the transmission of a virus. Yet while the monomeric shows fusiogenic activity, only the fibrillar form enhances viral transmission. The formation of these fibers is then critical to viral transmission. We see that the green tea compound EGCG can be used to both inhibit and disaggregate the amyloid fibers of SEVI due to its polyphenolic nature, while preformed fibrils of the E. coli produced curlin protein are seen to enhance the formation of SEVI. Cofactors such as the SEVI fibers could explain why HIV is weak in vitro, yet AIDS continues to be a global pandemic.