Activity and structure of human (d)CTP deaminase CDADC1

Area of Science:

• Biochemistry
• Structural Biology
• Genetics

Background:

• CDADC1 (NYD-SP15) is an understudied vertebrate protein with a DCTD-like domain.
• Its precise enzymatic function and biological role remain largely unknown.

Purpose of the Study:

• To characterize the enzymatic activity and substrate specificity of human CDADC1.
• To elucidate the structural basis of substrate recognition and oligomerization.
• To investigate the in vivo relevance of CDADC1 through genetic studies in mice.

Main Methods:

• In vitro enzymatic assays to determine substrate preference.
• Cryo-electron microscopy (cryo-EM) to determine high-resolution structures.
• Genetic knockout experiments in mice.

Main Results:

• Human CDADC1 functions as a (deoxy)cytidine triphosphate deaminase with a preference for dCTP over CTP.
• Cryo-EM structures reveal substrate-induced oligomerization from trimers to hexamers.
• Mice lacking Cdadc1 are viable and surprisingly well-tolerated, even without Dctd.

Conclusions:

• CDADC1 is a dCTP-specific deaminase with a unique substrate-binding pocket and oligomerization mechanism.
• The enzyme's function is adaptable in vivo, suggesting functional redundancy or alternative pathways for dNTP metabolism.