8S9L

Structure of monomeric FAM111A SPD V347D Mutant

8S9L の概要

• エントリーDOI: 10.2210/pdb8s9l/pdb
• 分子名称: Serine protease FAM111A, SULFATE ION (3 entities in total)
• 機能のキーワード: protease, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 61866.19

構造登録者

Palani, S.,Alvey, J.A.,Cong, A.T.Q.,Schellenberg, M.J.,Machida, Y. (登録日: 2023-03-29, 公開日: 2024-03-20)

主引用文献

Palani, S.,Machida, Y.,Alvey, J.R.,Mishra, V.,Welter, A.L.,Cui, G.,Bragantini, B.,Botuyan, M.V.,Cong, A.T.Q.,Mer, G.,Schellenberg, M.J.,Machida, Y.J.
Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes.
Nat Commun, 15:2064-2064, 2024

PubMed Abstract: FAM111A, a serine protease, plays roles in DNA replication and antiviral defense. Missense mutations in the catalytic domain cause hyper-autocleavage and are associated with genetic disorders with developmental defects. Despite the enzyme's biological significance, the molecular architecture of the FAM111A serine protease domain (SPD) is unknown. Here, we show that FAM111A is a dimerization-dependent protease containing a narrow, recessed active site that cleaves substrates with a chymotrypsin-like specificity. X-ray crystal structures and mutagenesis studies reveal that FAM111A dimerizes via the N-terminal helix within the SPD. This dimerization induces an activation cascade from the dimerization sensor loop to the oxyanion hole through disorder-to-order transitions. Dimerization is essential for proteolytic activity in vitro and for facilitating DNA replication at DNA-protein crosslink obstacles in cells, while it is dispensable for autocleavage. These findings underscore the role of dimerization in FAM111A's function and highlight the distinction in its dimerization dependency between substrate cleavage and autocleavage.

PubMed: 38453899
DOI: 10.1038/s41467-024-46207-w

実験手法

X-RAY DIFFRACTION (1.85 Å)