A role for the transmembrane domain in the trimerization of the MHC class II-associated invariant chain

MHC class II and invariant chain (Ii) associate early in biosynthesis to fo rm a nonameric complex. Ii first assembles into a trimer and then associate s with three class II: cup heterodimers. Although the membrane-proroimal re gion of the Ii luminal domain is structurally disordered, the C-terminal se gment of the luminal domain is largely cu-helical and contains a major inte raction site for the Ii trimer. In this study, we show that the Ii transmem brane domain plays an important role in the formation of Ii trimers, The Ii transmembrane domain contains an unusual patch of hydrophilic residues nea r the luminal interface. Substitution of these polar residues with nonpolar amino acids resulted in a decrease in the efficiency of Ii trimerization a nd subsequent class ZI association. Moreover, N-terminal fragments of Ii we re found to trimerize independently of the luminal alpha-helical domain. Pr ogressive C-terminal truncations mapped a homotypic association site to We first 80 aa of Ii. Together, these results implicate We Ii transmembrane do main as a site of trimer interaction that can play an important role in the initiation of trimer formation.