Figure 8. Proposed model for concerted action between HOIL-1-interacting protein (HOIP) and heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1L) in heterotypic chain assembly.

HOIP and HOIL-1L assemble heterotypic chains through a Cys relay mechanism. HOIP forms a thioester bond to ubiquitin, which can be either transferred to a thioester bond on HOIL-1L or added to a nascent linear ubiquitin chain. HOIL-1L subsequently binds the linear ubiquitin chain through its Npl zinc finger (NZF) domain and branches it with ester linkages. The resulting heterotypic poly-ubiquitin chains contain predominantly linear linkages with ester-linked branches.