STRUCTURE-ACTIVITY RELATIONSHIP OF THE LEUCINE-BASED SORTING MOTIFS IN THE CYTOSOLIC TAIL OF THE MAJOR HISTOCOMPATIBILITY COMPLEX-ASSOCIATED INVARIANT CHAIN

The cytosolic tail of the major histocompatibility complex-associated invariant chain protein contains two Leu-based motifs that both mediate efficient sorting to the endocytic pathway, Nuclear magnetic resonance data on a peptide of 27 residues corresponding to the cytosolic tail of human invariant chain indicate that in water at pH 7.4 the membrane distal motif Leu(7)-Ile(8) lies within a nascent helix, while the membrane proximal motif Met(16)-Leu(17) is part of a turn. The presence of a small amount of methanol stabilizes an alpha helix from Gln(4) to Leu(17) with a kink on pro(15), Point mutations of the cytosolic tail of the protein suggest that amino-terminal residues located in spatial proximity to the Leu motifs contribute to efficient internalization and targeting to endosomes in transfected COS cells, Residues on the spatially opposite side of the Leu motifs were, on the other hand, mutated with no measurable effect on targeting, Structural and biological data thus suggest that the signals are not continuous but consist of ''signal patches'' formed by the three-dimensional structure of the cytosolic tail of invariant chain.