Sequence-based identification of amyloidogenic β-hairpins reveals a prostatic acid phosphatase fragment promoting semen amyloid formation

被引：2

作者：

Heid, Laetitia F. ^{[1
]}

Agerschou, Emil Dandanell ^{[1
]}

Orr, Asuka A. ^{[2
]}

Kupreichyk, Tatsiana ^{[1
,3
]}

Schneider, Walfried ^{[1
]}

Woerdehoff, Michael M.

Schwarten, Melanie ^{[3
]}

Willbold, Dieter ^{[1
,3
]}

Tamamis, Phanourios ^{[2
,4
]}

Stoldt, Matthias ^{[3
]}

Hoyer, Wolfgang ^{[1
,3
]}

机构：

[1] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, D-40204 Dusseldorf, Germany

[2] Texas A&M Univ, Artie McFerrin Dept Chem Engn, College Stn, TX 77843 USA

[3] Forschungszentrum Julich, Inst Biol Informat Proc IBI 7 & JuStruct, Julich Ctr Struct Biol, D-52425 Julich, Germany

[4] Texas A&M Univ, Dept Mat Sci & Engn, College Stn, TX 77843 USA

来源：

COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL | 2024年 / 23卷

基金：

欧洲研究理事会;

关键词：

Amyloid; beta-hairpin; Protein misfolding; Protein aggregation; Proteopathy; Semen amyloid; PROTEIN AGGREGATION; PEPTIDE; BINDING; STABILIZATION; NUCLEATION; INHIBITOR; DYNAMICS; MONOMERS; REGIONS; DIMERS;

D O I：

10.1016/j.csbj.2023.12.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

beta-Structure-rich amyloid fibrils are hallmarks of several diseases, including Alzheimer's (AD), Parkinson's (PD), and type 2 diabetes (T2D). While amyloid fibrils typically consist of parallel beta-sheets, the anti-parallel beta-hairpin is a structural motif accessible to amyloidogenic proteins in their monomeric and oligomeric states. Here, to investigate implications of beta-hairpins in amyloid formation, potential beta-hairpin-forming amyloidogenic segments in the human proteome were predicted based on sequence similarity with beta-hairpins previously observed in A beta, alpha-synuclein, and islet amyloid polypeptide, amyloidogenic proteins associated with AD, PD, and T2D, respectively. These three beta-hairpins, established upon binding to the engineered binding protein beta-wrapin AS10, are characterized by proximity of two sequence segments rich in hydrophobic and aromatic amino acids, with high beta-aggregation scores according to the TANGO algorithm. Using these criteria, 2505 potential beta-hairpin-forming amyloidogenic segments in 2098 human proteins were identified. Characterization of a test set of eight protein segments showed that seven assembled into Thioflavin T-positive aggregates and four formed beta-hairpins in complex with AS10 according to NMR. One of those is a segment of prostatic acid phosphatase (PAP) comprising amino acids 185-208. PAP is naturally cleaved into fragments, including PAP(248-286) which forms functional amyloid in semen. We find that PAP(185-208) strongly decreases the protein concentrations required for fibril formation of PAP(248-286) and of another semen amyloid peptide, SEM1(86-107), indicating that it promotes nucleation of semen amyloids. In conclusion, beta-hairpin-forming amyloidogenic protein segments could be identified in the human proteome with potential roles in functional or disease-related amyloid formation.

引用

页码：417 / 430

页数：14