8CIH

Structure of FL CINP

Summary for 8CIH

• Entry DOI: 10.2210/pdb8cih/pdb
• Descriptor: Cyclin-dependent kinase 2-interacting protein, SODIUM ION (3 entities in total)
• Functional Keywords: alpha-helical structure, protein complex subunit, dna replication, replication
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 48998.89

Authors

Foglizzo, M.,Zeqiraj, E. (deposition date: 2023-02-09, release date: 2024-02-21, Last modification date: 2024-05-08)

Primary citation

Krishnamoorthy, V.,Foglizzo, M.,Dilley, R.L.,Wu, A.,Datta, A.,Dutta, P.,Campbell, L.J.,Degtjarik, O.,Musgrove, L.J.,Calabrese, A.N.,Zeqiraj, E.,Greenberg, R.A.
The SPATA5-SPATA5L1 ATPase complex directs replisome proteostasis to ensure genome integrity.
Cell, 187:2250-, 2024

PubMed Abstract: Ubiquitin-dependent unfolding of the CMG helicase by VCP/p97 is required to terminate DNA replication. Other replisome components are not processed in the same fashion, suggesting that additional mechanisms underlie replication protein turnover. Here, we identify replisome factor interactions with a protein complex composed of AAA+ ATPases SPATA5-SPATA5L1 together with heterodimeric partners C1orf109-CINP (55LCC). An integrative structural biology approach revealed a molecular architecture of SPATA5-SPATA5L1 N-terminal domains interacting with C1orf109-CINP to form a funnel-like structure above a cylindrically shaped ATPase motor. Deficiency in the 55LCC complex elicited ubiquitin-independent proteotoxicity, replication stress, and severe chromosome instability. 55LCC showed ATPase activity that was specifically enhanced by replication fork DNA and was coupled to cysteine protease-dependent cleavage of replisome substrates in response to replication fork damage. These findings define 55LCC-mediated proteostasis as critical for replication fork progression and genome stability and provide a rationale for pathogenic variants seen in associated human neurodevelopmental disorders.

PubMed: 38554706
DOI: 10.1016/j.cell.2024.03.002

Experimental method

X-RAY DIFFRACTION (2 Å)