A
serine protease,
motopsin (prss12), plays a significant role in cognitive function and the development of the brain, since the loss of
motopsin function causes severe
mental retardation in humans and enhances social behavior in mice.
Motopsin is activity-dependently secreted from neuronal cells, is captured around the synaptic cleft, and cleaves a
proteoglycan,
agrin. The multi-domain structure of
motopsin, consisting of a
signal peptide, a
proline-rich domain, a kringle domain, three
scavenger receptor cysteine-rich domains, and a
protease domain at the C-terminal, suggests the interaction with other molecules through these domains. To identify a
protein interacting with
motopsin, we performed yeast two-hybrid screening and found that seizure-related gene 6 (sez-6), a transmembrane
protein on the plasma membrane of neuronal cells, bound to the
proline-rich/kringle domain of
motopsin. Pull-down and immunoprecipitation analyses indicated the interaction between these
proteins. Immunocytochemical and immunohistochemical analyses suggested the co-localization of
motopsin and sez-6 at neuronal cells in the developmental mouse brain and at motor neurons in the anterior horn of human spinal cords. Transient expression of
motopsin in neuro2a cells increased the number and length of neurites as well as the level of neurite branching. Interestingly, co-expression of sez-6 with
motopsin restored the effect of
motopsin at the basal level, while sez-6 expression alone showed no effects on cell morphology. Our results suggest that the interaction of
motopsin and sez-6 modulates the neuronal cell morphology.