Micellar TIA1 with folded RNA binding domains as a model for reversible stress granule formation
Micellar TIA1 with folded RNA binding domains as a model for reversible stress granule formation
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DOI：
10.1073/pnas.2007423117
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发表时间：
2020-12-15
影响因子：
11.1
通讯作者：
McDermott, Ann E.
中科院分区：
文献类型：
--
作者：
Fritzsching, Keith J.;Yang, Yizhuo;McDermott, Ann E.
TIA1是真核生物应激反应和应激颗粒形成的关键蛋白，其结构特征为全长。TIA1包含三个RNA识别基序(RRMS)和一个C-末端低复杂性结构域，有时被称为“Prion相关结构域”或与淀粉样蛋白的形成有关。在温和的条件下，全长(FL)小鼠TIA1自发地寡聚形成亚稳定的胶体状悬浮液。已知对功能至关重要的RRM2和RRM3在切除的结构域和这种寡聚体形式的apo fl TIA1中类似地折叠，基于核磁共振化学位移。相比之下，核磁共振没有检测到末端，不太可能是淀粉样蛋白。我们能够借助先前分配的RRM2，3分离结构域的溶液状态位移和同源建模来指定核磁共振位移。我们提出了一个Fl TIA1的胶束模型，其中RRM2和RRM3是共定位的、有序的、水合的，并且可用于核苷酸结合。同时，末端无序，相分离，使人联想到应力颗粒亚结构或纳米级液滴。
TIA1, a protein critical for eukaryotic stress response and stress granule formation, is structurally characterized in full-length form. TIA1 contains three RNA recognition motifs (RRMs) and a C-terminal low-complexity domain, sometimes referred to as a "prion-related domain" or associated with amyloid formation. Under mild conditions, full-length (fl) mouse TIA1 spontaneously oligomerizes to form a metastable colloid-like suspension. RRM2 and RRM3, known to be critical for function, are folded similarly in excised domains and this oligomeric form of apo fl TIA1, based on NMR chemical shifts. By contrast, the termini were not detected by NMR and are unlikely to be amyloid-like. We were able to assign the NMR shifts with the aid of previously assigned solution-state shifts for the RRM2,3 isolated domains and homology modeling. We present a micellar model of fl TIA1 wherein RRM2 and RRM3 are colocalized, ordered, hydrated, and available for nucleotide binding. At the same time, the termini are disordered and phase separated, reminiscent of stress granule substructure or nanoscale liquid droplets.