TI  - <prot>TrkA</prot> amino acids controlling specificity for nerve growth factor.
PG  - 7870-7
AB  -  Neurotrophins  are important for the development and maintenance of the
      vertebrate nervous system, mediating their signal into the cell by
      specific interaction with  tyrosine kinase receptors of the Trk family. The
      extracellular portion of the Trk receptors has been previously proposed to
      consist of a cysteine-rich motif, a leucine-rich motif, a second
      cysteine-rich motif followed by two immunoglobulin-like domains. Earlier
      studies have shown that a major  neurotrophin -binding site in the Trk 
      receptors resides in the second immunoglobulin-like domain. Although the
      individual amino acids in <prot>TrkA</prot>  involved in binding to  <prot>nerve growth factor</prot>(<prot>NGF</prot>)  and those in  <prot>TrkC</prot> involved in binding to  <prot>neurotrophin-3</prot> have been
      mapped in this domain, the Trk amino acids that provide specificity
      remained unclear. In this study, a minimum set of residues in the human
      <prot>TrkC</prot> second immunoglobulin-like domain, which does not bind <prot>nerve growth
      factor</prot> (<prot>NGF</prot>), were substituted with those from human <prot>TrkA</prot>. The resulting
      Trk variant recruited binding of <prot>NGF</prot> equivalent to <prot>TrkA</prot>, maintained
      <prot>neurotrophin-3</prot> binding equivalent to <prot>TrkC</prot>, and also bound <prot>brain-derived
      neurotrophin</prot>, although with lower affinity compared with <prot>TrkB</prot>. This
      implies that the amino acids in the second immunoglobulin-like domain that
      determine Trk specificity are distinct for each Trk.
AD  - Departments of Immunology, Genentech Inc., South San Francisco, California
