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研究生： 郭邦賢
Kuo, Pan-Hsien
論文名稱： Structural insights into TDP-43 in nucleic acid binding and domain interactions
TDP-43 與核酸結合及特殊區域間之相互作用的結構研究
指導教授： 袁小琀
Yuan, Hanna S.
呂平江
Lyu, Ping-Chiang
口試委員:
學位類別： 博士
Doctor
系所名稱： 生命科學暨醫學院 - 生物資訊與結構生物研究所
Institute of Bioinformatics and Structural Biology
論文出版年： 2011
畢業學年度： 99
語文別： 英文
論文頁數： 69
中文關鍵詞： 結構 、核酸 、纖維囊腫 、神經退化性疾病 、纖維
外文關鍵詞： TDP-43, FTLD, ALS, cystic fibrosis, fiber
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    • TDP-43為一可引起疾病之蛋白質，TDP-43與含有UG-rich之RNA結合的功能，與纖維囊腫（cystic fibrosis)有關。TDP-43也會形成聚合體，而與額顳葉退化型失智症（frontotemporal lobar degeneration, FTLD)及肌萎縮性脊髓側索硬化症(漸凍人) (amyotrophic lateral sclerosis, ALS)等神經退化性疾病有關。瞭解TDP-43如何與DNA和RNA結合，如何形成聚合體，是瞭解此蛋白質與疾病間關係的關鍵。在此論文中，我們發現含有兩個RRM區域的TDP-43為一之二聚物，RRM1和RRM2區域都可以與核酸分子結合。我們測定了位於TDP-43 C端之RRM2結構域與單股DNA之複合晶體結構，其解析度為1.65 Å。蛋白質結構說明了為何TDP-43傾向與含有TG之DNA序列或含有UG之RNA序列結合。除此之外，不同於典型之RRM結構，TDP-43 之RRM2擁有一額外的b-strand (b4)。我們經由circular dichroism及dynamic light scattering實驗發現，伴隨著溫度上升RRM2可形成含有b-strand結構的高分子量的聚合體。然而，單點突變的實驗結果並不支持額外的□4是如結構所示扮演蛋白質與蛋白質交互作用重要角色的這個推論。另一方面，RRM2的b3以及b5會形成直徑約5-10nm的纖維結構，這個結果顯示b3及b5可能才是參與高分子量的聚合體的形成主因。我們推論RRM2區域的結構會經由加溫或不正常的斷裂而鬆散開來形成聚合體。根據這些結果除了可以了解TDP-43與核酸結合的特性及RRM2自我結合的模式，也可以提供一個分子模型而了解TDP-43在纖維囊腫及神經退化性疾病中所扮演的角色。

    TDP-43 is a pathogenic protein: its normal function in binding to UG-rich RNA is related to cystic fibrosis, and inclusion of its C-terminal fragments in brain cells is directly linked to neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). To understand the role of TDP-43 in these human diseases, it is important to reveal how TDP-43 binds DNA and RNA, and how it forms inclusions. Here our biochemical data showed that TDP-43 is a dimeric protein with two RRM domains, both involved in DNA and RNA binding. We have determined the crystal structure of the C-terminal RRM2 domain of TDP-43 in complex with a single-stranded DNA at a resolution of 1.65 Å. The crystal structure reveals the basis of TDP-43’s TG/UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM fold with an additional b-strand (b4). We also found that RRM2 domain formed high-order assembly with retained b-strand structure when the temperature was increased, as monitored by circular dichroism and dynamic light scattering. However, the mutagenesis studies did not support that b4 participated in the protein-protein interactions as shown in the crystal packing environment. On the other hand, b3 and b5 of RRM2 domain could form fibrils with a width of 5-10 nm as shown in electron microscopy, suggesting that these two b-strands may be involved in forming high-order assembly. We suggest that the RRM2 domain of TDP-43 can be unfolded and the exposed b-strands are then aggregated into high-order assembly to initiate protein inclusions. These studies thus characterize the recognition between TDP-43 and nucleic acids and the possible mode of TDP-43 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy.

    中文摘要 1 Summary 2 1. Introduction 3 1.1 Domain structure of TDP-43 3 1.1.1 TDP-43 is a DNA-binding protein functioning as a transcriptional factor 4 1.1.1.1 TDP-43 represses the transcription of HIV-1 gene 4 1.1.1.2 TDP-43 represses the transcription of SP-10 gene 5 1.1.1.3 TDP-43 regulates the expression of human cyclin- dependent kinase 6 (Cdk6) 6 1.1.2 TDP-43 is a RNA-binding protein involved in splicing and translation regulation 6 1.1.2.1 TDP-43 is a splicing factor of CFTR gene 6 1.1.2.2 TDP-43 is a splicing factor of apoA-II gene 7 1.1.2.3 TDP-43 is involved in regulating the stability of mRNA 8 1.1.2.4 TDP-43 is a neuronal activity-responsive factor 9 1.1.3 TDP-43 is involved in neurodegenerative proteinopathy 9 1.1.3.1 Identification of TDP-43 as a major disease protein in FTLD and ALS 9 1.1.3.1.1 Frontotemporal Lobar Degeneration (FTLD) 11 1.1.3.1.2 Amyotrophic Lateral Sclerosis (ALS) 11 1.1.3.2 The pathobiology of TDP-43 13 1.1.3.3 TDP-43 inclusions comprise granules and filaments 14 2. The specific aims of the study 14 3. Material and Methods 15 3.1 Protein expression and purification 15 3.2 TDP-43 expresses in 293T cells 16 3.3 Filter binding assay 17 3.4 Circular dichroism 17 3.5 Dynamics light scattering (DLS) 18 3.6 Crystallization, structural determination and refinement 18 3.7 Fibril formation 19 3.8 Site-directed mutagenesis 19 3.9 Electron microscopy 20 4. Results 20 4.1 TDP43s is a dimer with four RRM domains 20 4.2 TDP-43s binds ssDNA and dsDNA with preference for TG- rich sequences 21 4.3 TDP-43s prefers to bind UG-rich RNA 22 4.4 Overall crystal structure of RRM2-DNA complex 23 4.5 Specific interactions between TDP-43 and TG sequence 25 4.6 RRM2 domain is highly thermal stable 26 4.7 RRM2 domain forms a high-order assembly in solution 26 4.8 b2 and b1 in RRM2 are likely not involved in high- order assembly formation 27 4.9. Two b-strands of RRM2 can form fibril-like structure 28 5. Discussion 29 5.1 Both RRM1 and RRM2 of TDP-43 are involved in site- specific DNA/RNA interactions 29 5.2 TDP-43 RRM2 domain has a unique atypical RRM fold 30 5.3 A new model of how TDP-43 forms aggregations 31 6. Acknowledgements 32

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