| Aspect | Summary | Key details / examples | Evidence |
|---|---|---|---|
| Gene/protein identity | **CRBN (cereblon), UniProt Q96SW2, human** is the substrate receptor of the **CRL4^CRBN** E3 ubiquitin ligase complex | CRBN associates with **DDB1, CUL4A/4B, and RBX1/ROC1** to confer substrate specificity for ubiquitination and subsequent proteasomal degradation | (pqac-00000001, pqac-00000002, pqac-00000005, pqac-00000010) |
| Primary molecular function | **Substrate recognition adaptor/receptor** in a Cullin-RING ligase, rather than a catalytic enzyme itself | CRBN recruits substrates to the CRL4 core, enabling E2-dependent ubiquitin transfer; drug binding can reprogram substrate specificity toward neosubstrates | (pqac-00000001, pqac-00000005, pqac-00000010, pqac-00000011) |
| Structural organization | CRBN contains **three folded domains** plus an N-terminal region important for conformational control | **Lon protease-like domain (Lon)**, **helical bundle (HB)** that docks to DDB1, and **C-terminal thalidomide-binding domain (TBD)** harboring the ligand pocket; ligand binding promotes open-to-closed rearrangement | (pqac-00000000, pqac-00000009, pqac-00000010) |
| Conformational mechanism | Small-molecule binding regulates CRBN conformation and thereby substrate recruitment | CELMoD/IMiD binding to the TBD is sufficient to trigger transition from an **open** to **closed** CRBN state; stable neosubstrate engagement requires the closed state | (pqac-00000009, pqac-00000010) |
| Endogenous substrate recognition | CRBN recognizes native cellular substrates in the absence of exogenous drugs, although the endogenous substrate landscape is still being defined | Reviews summarize **MEIS2** and **SLO1** as endogenous CRL4^CRBN substrates; experimental work identified **ILF2** as a CRBN-interacting substrate whose ubiquitination and proteasomal degradation are promoted by CRBN | (pqac-00000005, pqac-00000007) |
| Endogenous substrates highlighted in this report | Representative native targets linked to physiological CRBN activity | **MEIS2**; **SLO1**; **ILF2** (with ILF2 K45 implicated as a key ubiquitination site in one study) | (pqac-00000005, pqac-00000007) |
| Drug-induced neosubstrates | IMiDs/CELMoDs convert CRBN into a recruiter of **neosubstrates** that are not normally targeted in the same way | Canonical examples include **IKZF1 (Ikaros)** and **IKZF3 (Aiolos)**; additional therapeutically or biologically important neosubstrates include **CK1α**, **GSPT1**, and teratogenicity-linked **SALL4** | (pqac-00000004, pqac-00000005, pqac-00000008, pqac-00000011) |
| Degron / binding principles | Many CRBN molecular-glue neosubstrates use a recognizable structural motif | Structural analyses describe a **G-loop** motif whose backbone and side chains contact CRBN residues such as **N351, H357, and W400** in drug-stabilized ternary complexes; this explains selectivity rules for many neosubstrates | (pqac-00000008) |
| Subcellular localization | CRBN functions in **both nucleus and cytoplasm** | Prior work summarized in later studies notes CRBN localization in both compartments; ternary complex imaging showed CRBN-based degraders can operate mainly in the **nucleus** for BRD4-directed degradation and in the **cytoplasm** for FKBP12-directed degradation | (pqac-00000006, pqac-00000007) |
| Role in IMiD mechanism | CRBN is the **direct target** of thalidomide-class drugs and the central mediator of their downstream effects | Thalidomide/lenalidomide/pomalidomide bind the TBD; this rewires CRBN substrate specificity, causing ubiquitination and degradation of selected neosubstrates and explaining major therapeutic as well as teratogenic effects | (pqac-00000000, pqac-00000004, pqac-00000005, pqac-00000011) |
| Therapeutic relevance | CRBN is a major E3 ligase co-opted in modern targeted protein degradation | A large fraction of clinical PROTACs/degraders recruit CRBN; next-generation CELMoDs such as **mezigdomide** exploit improved CRBN engagement and neosubstrate degradation potency | (pqac-00000001, pqac-00000010) |


*Table: This table summarizes the core functional annotation of human cereblon (CRBN), including its structural domains, molecular role in CRL4 ubiquitin ligase complexes, key endogenous and drug-induced substrates, localization, and importance in IMiD pharmacology. It is useful as a compact evidence-backed reference for the main biological and translational features of CRBN.*