Figure 6.

Mechanisms for inactivating IRP1 RNA-binding activity: IRP1 is iron-regulated by two mechanisms. Cluster-dependent regulation (left arrow) is reversible and allows for the maintenance of a large reserve of IRE-binding activity as c-acon. The cluster-independent mechanism (right arrow) is not reversible since IRP1 is degraded, but also provides a means for growth factors and other extracellular agents to uncouple IRP1 from regulation by the Fe–S cluster in order to alter the sensitivity and timing of the response of IRP1 to iron. S138 phosphorylation can activate RNA binding by destabilizing the Fe–S cluster, reducing the accumulation of IRP1 in the c-acon form. However, when iron levels rise to a sufficient level, S138 phosphorylated IRP1 is degraded.