Abstract
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.
Highlights
Human CDC73, known as parafibromin, is a human nuclear protein encoded by the cell division cycle 73 (CDC73) gene which is located on chromosome 1q31.21,2
A number of missense variants of Human CDC73 (hCDC73) have been found in hyperparathyroidism-jaw tumor (HPT-JT) and other diseases, only a few of them, including K34Q, I60N, L64P and R91P, have been shown to be pathogenic (Supplementary Table S1)
To understand how the CDC73 N-terminal domain contributes to CDC73 functions and how CDC73 pathogenic mutations may lead to HPT-JT and other diseases, we have characterized the structural features of the CDC73 N-terminal regions and revealed a previously unidentified N-terminal globular domain
Summary
Human CDC73 (hCDC73), known as parafibromin, is a human nuclear protein encoded by the cell division cycle 73 (CDC73) gene which is located on chromosome 1q31.21,2. In some other occasions, CDC73 possesses oncogenic features It can serve as a transcriptional coactivator of the Wnt/β-catenin signaling pathway by directly interacting with β-catenin in the nucleus. Notch pathway and plays important roles during embryogenesis and organogenesis22,23 Both tumor-suppressing and oncogenic effects of CDC73 rely on the N-terminal portion of hCDC7318,20. The L64P mutation found in HPT-JT patients was found to be able to retain nuclear expression and form PAF1C, but showed reduced interaction with the Set histone methyltransferase complex and decreased its HMTase activity. To understand how the CDC73 N-terminal domain contributes to CDC73 functions and how CDC73 pathogenic mutations may lead to HPT-JT and other diseases, we have characterized the structural features of the CDC73 N-terminal regions and revealed a previously unidentified N-terminal globular domain. Our study provides novel insights into CDC73 function and molecular mechanisms of HPT-JT mutants
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