Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Alkermes Inc. 852 Winter Street, Waltham, MA 02451.
FEMS Yeast Res. 2018 Sep 1;18(6). doi: 10.1093/femsyr/foy059.
Yeast prions are self-templating protein-based mechanisms of inheritance whose conformational changes lead to the acquisition of diverse new phenotypes. The best studied of these is the prion domain (NM) of Sup35, which forms an amyloid that can adopt several distinct conformations (strains) that confer distinct phenotypes when introduced into cells that do not carry the prion. Here, we investigate the structure of NM fibrils templated into the prion conformation with cellular lysates. Our electron microscopy studies reveal that NM fibrils that confer either a strong or a weak prion phenotype are both mixtures of thin and thick fibrils that result from differences in packing of the M domain. Strong NM fibrils have more thin fibrils and weak NM fibrils have more thick fibrils. Interestingly, both mass per length and solid state NMR reveal that the thin and thick fibrils have different underlying molecular structures in the prion strain variants that do not interconvert.
酵母朊病毒是自我模板化的基于蛋白质的遗传机制，其构象变化导致获得多种新的表型。这些朊病毒中研究得最好的是 Sup35 的朊病毒结构域 (NM)，它形成淀粉样纤维，可以采用几种不同的构象（菌株），当引入不携带朊病毒的细胞时，赋予不同的表型。在这里，我们用细胞裂解物研究了在朊病毒构象中模板化的 NM 纤维的结构。我们的电子显微镜研究表明，赋予强或弱朊病毒表型的 NM 纤维都是由 M 结构域包装差异导致的薄纤维和厚纤维的混合物。强 NM 纤维具有更多的薄纤维，弱 NM 纤维具有更多的厚纤维。有趣的是，质量/长度比和固态 NMR 都表明，在不相互转化的朊病毒菌株变体中，薄纤维和厚纤维具有不同的基础分子结构。
