Structural Modulation of Human Amylin Protofilaments by Naturally Occurring Mutations

被引:12
|
作者
Tofoleanu, Florentina [1 ,2 ]
Yuan, Ye [3 ,4 ]
Pickard, Frank C. [1 ]
Tywoniuk, Bartlomiej [3 ,4 ]
Brooks, Bernard R. [1 ]
Buchete, Nicolae-Viorel [3 ,4 ]
机构
[1] NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA
[2] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA
[3] Univ Coll Dublin, Inst Discovery, Dublin 4, Ireland
[4] Univ Coll Dublin, Sch Phys, Dublin 4, Ireland
来源
JOURNAL OF PHYSICAL CHEMISTRY B | 2018年 / 122卷 / 21期
基金
美国国家卫生研究院;
关键词
ISLET AMYLOID POLYPEPTIDE; MOLECULAR-DYNAMICS SIMULATION; AMINO-ACID-RESIDUES; ALZHEIMERS-DISEASE; DIABETES-MELLITUS; LIPID-MEMBRANES; BETA PEPTIDE; RAT AMYLIN; IN-VITRO; FIBRILS;
D O I
10.1021/acs.jpcb.7b12083
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
Human islet amyloid polypeptide (hIAPP), also known as amylin, is a 37-amino-acid peptide, co-secreted with insulin, and widely found in fibril form in type-2 diabetes patients. By using allatom molecular dynamics simulations, we study hIAPP fibril segments (i.e., fibrillar oligomers) formed with sequences of naturally occurring variants from cat, rat, and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hIAPP fibril models built from solid-state NMR data. Results from this study are in agreement with experimental observations regarding their respective relative aggregation propensities. We analyze in detail the specific structural characteristics and infer mechanisms that modulate the conformational stability of amylin fibrils. Results provide a platform for further studies and the design of new drugs that could interfere with amylin aggregation and its cytotoxicity. One particular mutation, N31K, has fibril-destabilizing properties, and could potentially improve the solubility of therapeutic amylin analogs.
引用
收藏
页码:5657 / 5665
页数:9
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