Structural biology of axon guidance
Netrin-1 is a prototypical axon guidance cue. When it interacts with its receptor DCC (Deleted in Colorectal Cancer) expressed on an axon’s growth cone surface, it will stimulate axon attraction. If another receptor, UNC5 co-expresses on axon surface with DCC, Netrin-1 will bind both DCC and UNC5, the activated heterodimeric receptors will result in axon repulsion. We have determined a crystal structure of Netrin-1 in complex with the membrane-proximal domains of DCC, the fibronectin type III domain 5 and 6 (FN5-FN6). The structure shows one Netrin-1 bound to two DCC molecules. Combined with functional assays, we have presented a proposal on how Netrin-1 can perform its bi-function, attraction and repulsion.
Our follow-up data show that after Netrin-1 brings two DCC close enough, two DCC cytoplasmic tails can dimerize with the focal adhesion target (FAT) domain of focal adhesion kinase (FAK) as the initial step of signaling cascade, eventually causing axon attraction.
Our follow-up data show that after Netrin-1 brings two DCC close enough, two DCC cytoplasmic tails can dimerize with the focal adhesion target (FAT) domain of focal adhesion kinase (FAK) as the initial step of signaling cascade, eventually causing axon attraction.