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Smad proteins are important intracellular mediators of TGF-β signalling, which transmit signals directly from cell surface receptors to the nucleus. The MH1 domain of Smad plays a key role in DNA recognition. Two types of DNA sequence were identified as Smad binding motifs: the Smad binding element (SBE) and the GC-rich sequence. Here we report the first crystal structure of the Smad5 MH1 domain in complex with the GC-rich sequence. Compared with the Smad5-MH1/SBE complex structure, the Smad5 MH1 domain contacts the GC-rich site with the same β-hairpin, but the detailed interaction modes are different. Conserved β-hairpin residues make base specific contacts with the minimal GC-rich site, 5′-GGC-3′. The assembly of Smad5-MH1 on the GC-rich DNA also results in distinct DNA conformational changes. Moreover, the crystal structure of Smad5-MH1 in complex with a composite DNA sequence demonstrates that the MH1 domain is targeted to each binding site (GC-rich or SBE) with modular binding modes, and the length of the DNA spacer affects the MH1 assembly. In conclusion, our work provides the structural basis for the recognition and binding specificity of the Smad MH1 domain with the DNA targets.

Background Fourth branchial apparatus anomalies, are rare clinical entities, and present as complex cysts, sinuses and fistulae in the neck that can be difficult to manage. Methods This is a retrospective review of a series of consecutive patients with fourth branchial apparatus anomalies treated at Department of Otolaryngology Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, from Apr 2014 to Nov 2019. Results Ten patients with fourth branchial apparatus anomalies were identified, including 8 patients with fourth branchial fistula, and 2 patients with fourth branchial pouch sinus. There were 6 female patients and 4 male patients. Their age was from 6 years old to 39 years old (average age 20.4 years old, median age was 21 years old). All 8 fistulae were on the left side, while 2 pouch sinuses were both on the right side. Pre-operative examination with fiberoptic laryngoscope, barium swallow X-ray, CT or MRI identified internal orifice at pyriform fossa apex in 8 (80%) patients. All patients underwent challenging surgical resection by the senior author. Intra-operative direct laryngoscope confirmed or identified internal orifice in 9 (90%) patients. The tracts were all followed to the vicinity of inferior cornu of the thyroid cartilage and the cricothyroid space. Complete resection of cervical lesions and their attachment to hypopharynx were achieved in 9 cases. No complication occurred. One recurrence was detected, in the only patient whose internal orifice could not be located pre- or intra-operatively, and the hypopharyngeal attachment could not be removed. Conclusions Direct laryngoscopy under general anesthesia is a reliable method of diagnosis for the fourth branchial apparatus anomalies. Complete surgical removal of fourth branchial apparatus anomalies, including their hypopharyngeal attachment, is the treatment of choice, and the key to prevent recurrence.

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