Structure and function of the iron-regulatory protein, repulsive guidance molecule c / hemojuvelin

Iron homeostasis depends on tightly regulated mechanisms that prevent both deficiency and toxic iron overload. Mutations in RGMc/HJV cause juvenile hemochromatosis, a severe early‑onset iron‑loading disorder marked by reduced hepcidin expression. This work investigates RGMc function using structure‑function analyses, revealing that full-length and soluble RGMc isoforms act as potent antagonists of BMP2‑ and BMP6‑mediated signaling. Using an MS3‑based disulfide mapping approach, we identified disulfide bonds in IGFBP‑5 and uncovered two distinct oxidation‑dependent disulfide patterns in RGMc. These findings provide new insight into RGMc structure and its role in iron regulation.