Rotational coupling of the transmembrane and kinase domains of the Neu receptor tyrosine kinase

Ligand binding to receptor tyrosine kinases (RTKs) regulates receptor dimer ization and activation of the kinase domain. To examine the role of the tra nsmembrane domain in regulation of RTK activation, we have exploited a simp lified transmembrane motif, [VVVEVVV](n), previously shown to activate the Neu receptor. Here we demonstrate rotational linkage of the transmembrane d omain with the kinase domain, as evidenced by a periodic activation of Neu as the dimerization motif is shifted across the transmembrane domain. These results indicate that activation requires a specific orientation of the ki nase domains with respect to each other. Results obtained with platelet-der ived growth factor receptor-beta suggest that this rotational linkage of th e transmembrane domain to the kinase domain may be a general feature of RTK s. These observations suggest hat activating mutations in RTK transmembrane and juxtamembrane domains will be limited to those residues that position the kinase domains in an allowed rotational conformation.