Cell Metab. 19, 445–457 (2014)

Credit: ELSEVIER

The delivery of assembled Fe-S clusters onto mitochondrial proteins is performed by a protein escort complex consisting of a chaperone (HSPA9), co-chaperone (HSC20) and the scaffold ISCU. However, it was unclear how this escort complex recognized protein targets. Maio et al. performed a yeast two-hybrid screen to identify binding partners of the co-chaperone, HSC20. They found that succinate dehydrogenase subunit B (SDHB), an Fe-S–containing electron transport chain complex II protein, interacted with HSC20 as part of an intermediate complex (designated as CIIb), which predated the fully assembled complex II. The incorporation of Fe-S clusters onto SDHB was thought to be a prerequisite for complex II maturation. Consistent with this, knockdown of HSC20 or HSPA9 blocked SDHB incorporation into complex II, resulting in a loss of complex II formation and activity. Deletion analysis of SDHB revealed two unique L(I)YR motifs that mediate binding to the C terminal of HSC20. Although these motifs were not sufficient for HSC20 binding, the N-terminal L(I)YR motif was critical for linking SDHB to the Fe-S–containing complex and ensuring SDHB incorporation into complex II. Interestingly, additional HSC20 binding proteins found in electron transport chain complex I and III have L(I)YR motifs, suggesting that this recognition motif may be a generalizable mechanism to ensure proper Fe-S delivery.