5YDF

Crystal structure of a disease-related gene, hCDC73(1-100)

5YDF の概要

• エントリーDOI: 10.2210/pdb5ydf/pdb
• 分子名称: Parafibromin (2 entities in total)
• 機能のキーワード: tumor suppressor, cancer, transcription
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus : Q6P1J9
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 23300.70

構造登録者

Sun, W.,Kuang, X.L.,Liu, Y.P.,Tian, L.F.,Yan, X.X.,Xu, W.Q. (登録日: 2017-09-13, 公開日: 2017-12-20, 最終更新日: 2024-03-27)

主引用文献

Sun, W.,Kuang, X.L.,Liu, Y.P.,Tian, L.F.,Yan, X.X.,Xu, W.
Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome
Sci Rep, 7:15638-15638, 2017

PubMed 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.

PubMed: 29142233
DOI: 10.1038/s41598-017-15715-9

実験手法

X-RAY DIFFRACTION (1.399 Å)