Characterization of ¦Â-domains in C-terminal fragments of TDP-43 by scanning tunneling microscopy

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• 作者：Meng Xu^a ; Li Zhu^b ; Jianghong Liu^b ; Yanlian Yang^a ; ^{yangyl@nanoctr.cn} ; Jane Y. Wu^b ; ^c ; Chen Wang^a ; ^{wangch@nanoctr.cn}
• 关键词：TAR DNA-binding protein 43 ; ¦Â-Domain ; STM ; Amyloid ; Fibril formation
• 刊名：Journal of Structural Biology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：181
• 期：1
• 页码：11-16
• 全文大小：1105 K

文摘

The TAR DNA-binding protein 43 (TDP-43) has been identified as a critical player in a range of neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recent discoveries demonstrate the important role of carboxyl-terminal fragments of TDP-43 in its proteinopathy. Herein, we report the characterization of ¦Â-domains in the C-terminal fragments of TDP-43 using scanning tunneling microscopy (STM). Careful comparison of the wild-type TDP-43 (Wt) and the three mutant TDP-43 peptides: an ALS-related mutant peptide: phosphorylated A315T mutant TDP-43 (A315T(p)) and two model peptides: A315T mutant TDP-43 (A315T), A315E mutant TDP-43 (A315E) reveals that A315T(p) has a longer core region of the ¦Â-domain than Wt. A315E possesses the longest core region of the ¦Â-domain and A315T(p) mutant TDP-43 has the second longest core region of the ¦Â-domain. The core regions of the ¦Â-domains for A315T and Wt TDP-43 have the same length. This observation provides a supportive evidence of a higher tendency in beta-sheet formation of A315T(p) containing TDP-43 fragment, and structural mechanism for the higher cytotoxicity and accelerated fibril formation of the A315T(p) mutation-containing TDP-43 peptide as compared with Wt TDP-43.