Crystal structures of the neurotrophin-binding domain of TrkA, TrkB and TrkC

The Trk receptors and their neurotrophin ligands control development and ma intenance of the nervous system. The crystal structures of the ligand bindi ng domain of TrkA, TrkB, and TrkC were solved and refined to high resolutio n The domains adopt an immunoglobulin-like fold, but crystallized in all th ree instances as dimers with the N-terminal strand of each molecule replace d by the same strand of a symmetry-related mate. Models of the correctly fo lded domains could be constructed by changing the position of a single resi due, and the resulting model of the binding domain of 'TrkA is essentially identical with the bound structure as observed in a complex with nerve grow th factor. An analysis of the existing mutagenesis data for TrkA and TrkC i n light of these structures reveals the structural reasons for the specific ity among the Trk receptors, and explains the underpinnings of the multi-fu nctional ligands that have been reported. The overall structure of all thre e domains belongs to the I-set of immunoglobulin-like domains, but shows se veral unusual features, such as an exposed disulfide bridge linking two nei ghboring strands in the same beta-sheet. For all three domains, the residue s that deviate from the standard fingerprint pattern common to the I-set fa mily fall in the region of the ligand binding site observed in the complex. Therefore, identification of these deviations in the sequences of other im munoglobulin-like domain-containing receptors may help to identify their li gand binding site even in the absence of structural or mutagenesis data. (C ) 1998 Academic Press.