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Significance Transactivation response element (TAR) DNA-binding protein 43 (TDP-43) inclusion is a histological hallmark of FTLD-TDP and amyotrophic lateral sclerosis. Its N terminus was just revealed as a double-edged sword indispensable for both physiology and proteinopathy, but its structure remains unknown due to aggregation. Here we revealed (i ) the TDP-43 N terminus encodes a well-folded structure in equilibrium with its unfolded form; (ii ) despite previous failure in detecting sequence homology to ubiquitin, the folded state assumes a novel ubiquitin-like fold; and (iii ) this ubiquitin-like fold could bind ssDNA, thus representing the first capable of directly binding nucleic acid. Taken together, our results provide a molecular mechanism rationalizing the functional dichotomy of TDP-43 and further imply one therapeutic strategy for TDP-43–causing diseases.

TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA