Olfactomedin-1 Has a V-shaped Disulfide-linked Tetrameric Structure

Olfactomedin-1 (Olfm1; also known as noelin and pancortin) is a member of the olfactomedin domain-containing superfamily and a highly expressed neuronal glycoprotein important for nervous system development. It binds a number of secreted proteins and cell surface-bound receptors to induce cell signaling processes. Using a combined approach of x-ray crystallography, solution scattering, analytical ultracentrifugation, and electron microscopy we determined that full-length Olfm1 forms disulfide-linked tetramers with a distinctive V-shaped architecture. The base of the “V” is formed by two disulfide-linked dimeric N-terminal domains. Each of the two V legs consists of a parallel dimeric disulfide-linked coiled coil with a C-terminal β-propeller dimer at the tips. This agrees with our crystal structure of a C-terminal coiled-coil segment and β-propeller combination (Olfm1coil-Olf) that reveals a disulfide-linked dimeric arrangement with the β-propeller top faces in an outward exposed orientation. Similar to its family member myocilin, Olfm1 is stabilized by calcium. The dimer-of-dimers architecture suggests a role for Olfm1 in clustering receptors to regulate signaling and sheds light on the conformation of several other olfactomedin domain family members. Background: Olfactomedin-1 (Olfm1) is a secreted protein with diverse roles in the developing nervous system. Results: We provide the crystal structure of the disulfide-linked coiled coil and olfactomedin domain of Olfm1 and its full-length quaternary arrangement. Conclusion: Olfm1 forms disulfide-linked homotetramers with a V-shaped architecture and binds calcium. Significance: This arrangement suggests a role in receptor clustering and ion channel regulation.