Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome

• Published in: Scientific reports Vol. 7; no. 1; pp. 15638 - 9
• Main Authors: Sun, Wei, Kuang, Xiao-Lin, Liu, Yan-Ping, Tian, Li-Fei, Yan, Xiao-Xue, Xu, Wenqing
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 15.11.2017; Nature Publishing Group UK
• Subjects: c-Myc protein; Cell proliferation; Crystal structure; Cyclin D1; Hereditary diseases; Hydrophobicity; Hyperparathyroidism; Jaw; Missense mutation; Mutation; Myc protein; Protein folding; Proteolysis; Structure-function relationships; Thermal stability; Transcription elongation; Tumor suppressor genes; Wnt protein; β-catenin
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-15715-9

CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/β-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 Å resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases.