8S9K

Structure of dimeric FAM111A SPD S541A Mutant

Summary for 8S9K

• Entry DOI: 10.2210/pdb8s9k/pdb
• Descriptor: Serine protease FAM111A, GLYCEROL (3 entities in total)
• Functional Keywords: protease, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 127521.05

Authors

Palani, S.,Alvey, J.A.,Cong, A.T.Q.,Schellenberg, M.J.,Machida, Y. (deposition date: 2023-03-29, release date: 2024-03-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.72 Å)