Department of Chemistry, Stony Brook University, Nicolls Road, Stony Brook, New York 11790, United States.
Graduate Program in Biochemistry and Structural Biology, Stony Brook University, Stony Brook, New York 11790, United States.
Biochemistry. 2022 Nov 15;61(22):2531-2545. doi: 10.1021/acs.biochem.2c00470. Epub 2022 Oct 26.
Human islet amyloid polypeptide (hIAPP) plays a role in glucose regulation but forms pancreatic amyloid deposits in type 2 diabetes, and that process contributes to β-cell dysfunction. Not all species develop diabetes, and not all secrete an IAPP that is amyloidogenic under normal conditions, a perfect correlation currently exists between both. Studies of IAPPs from such organisms can provide clues about the high amyloidogenicity of hIAPP and can inform the design of soluble analogues of hIAPP. Sheep and goat IAPP are among the most divergent from hIAPP, with 13 and 11 substitutions, respectively, including an unusual Tyr to His substitution at the C-terminus. The properties of sheep and goat IAPP were examined in solution and in the presence of anionic vesicles, resulting in no observed amyloid formation, even at increased concentrations. Furthermore, both peptides are considerably less toxic to cultured β-cells than hIAPP. The effect of the Y37H replacements was studied in the context of hIAPP, as was a Y37R substitution. Buffer- and salt-dependent effects were observed. There was little impact on the time to form amyloid in phosphate-buffered saline; however, a significant deceleration was observed in Tris buffer, and amyloid formation was slower in the absence of added salt. The Y37H substitution had little impact on toxicity, while the Y37R replacement led to a 30% decrease in toxicity compared with that of hIAPP. The implications for the amyloidogenicity of hIAPP and the design of soluble analogues of the human peptide are discussed.
人胰岛淀粉样多肽（hIAPP）在葡萄糖调节中发挥作用，但在 2 型糖尿病中形成胰腺淀粉样沉积物，这一过程导致β细胞功能障碍。并非所有物种都会发生糖尿病，并非所有物种在正常条件下都会分泌具有淀粉样特性的 IAPP，目前这两者之间存在着完美的相关性。对这些生物体的 IAPP 研究可以为 hIAPP 的高淀粉样特性提供线索，并为 hIAPP 的可溶性类似物的设计提供信息。绵羊和山羊的 IAPP 与 hIAPP 的差异最大，分别有 13 个和 11 个取代，包括 C 末端不寻常的 Tyr 到 His 取代。在溶液中和带负电荷的囊泡存在下研究了绵羊和山羊 IAPP 的性质，即使在浓度增加的情况下，也没有观察到淀粉样形成。此外，与 hIAPP 相比，这两种肽对培养的β细胞的毒性要小得多。在 hIAPP 的背景下研究了 Y37H 取代的影响，以及 Y37R 取代的影响。观察到缓冲液和盐依赖性效应。在磷酸盐缓冲液中形成淀粉样的时间几乎没有影响；然而，在 Tris 缓冲液中观察到明显的减速，并且在没有添加盐的情况下淀粉样形成较慢。Y37H 取代对毒性几乎没有影响，而 Y37R 取代导致毒性比 hIAPP 降低了 30%。讨论了 hIAPP 淀粉样形成性和人肽可溶性类似物设计的意义。
