Cullins assemble the largest subfamily of E3 ubiquitin ligases. Pie chart of the numbers of human E3 ubiquitin ligases, estimated from the numerical distribution of genes predicted to encode E3 RING or HECT polypeptides or, in the case of CRLs, the substrate-recognition molecules that include F-box, SOCS, BTB with 3-box and DCAF proteins. Numbers refer to human gene numbers for F-box, SOCS, HECT, U-box and non-CRL RING proteins, derived from Li et al. . The estimation for the human DCAF family is described by Lee and Zhou . Kay Hofmann has kindly provided the tally of human genes encoding BTB and 3-box proteins (personal communication). The Hofmann estimation is based on the structural work from Schulman and colleagues , which identified a critical role for the 3-box in the assembly of CRL3 with the SPOP BTB protein. 72 BTB-only (without 3-box) genes have not been counted for the estimation of CRL3s.