CRADD

CRADD, also known as RAIDD (RIP-associated ICH-1/CED-3 homologous protein with a death domain), is an adaptor protein that participates in apoptotic signaling. It is encoded by the CRADD gene in humans and functions to relay signals that promote programmed cell death in response to cellular stress.

The CRADD protein features two key interaction motifs: a caspase recruitment domain (CARD) at the N-terminus and a death domain (DD) at the C-terminus. This structural arrangement enables CRADD to bridge caspases and other death-domain–containing proteins, integrating into specific signaling complexes involved in apoptosis.

A primary context for CRADD function is the PIDDosome, a multiprotein complex that includes PIDD, CRADD, and caspase-2. In this pathway, CRADD serves as an adaptor that facilitates the interaction between PIDD and caspase-2, leading to the activation of caspase-2. Activated caspase-2 can promote apoptosis and is linked to p53-dependent responses to DNA damage or centrosome abnormalities, contributing to genomic stability and proper cellular homeostasis during development.

CRADD is conserved across vertebrates and is predominantly cytoplasmic, with expression patterns reported in multiple tissues, including the developing brain. As a member of the death domain superfamily, CRADD participates in a broader network of adaptor proteins that regulate cell fate decisions through apoptotic signaling.

Clinical relevance: Pathogenic variants in CRADD have been associated with neurodevelopmental disorders, including autosomal recessive intellectual disability and brain malformations in some families. The full spectrum of CRADD-related conditions and their prevalence continue to be investigated as researchers better understand the role of the PIDDosome and caspase-2 signaling in human development.