Both chains of HLA-DR bind to the membrane with a penultimate hydrophobic region and the heavy chain is phosphorylated at its hydrophilic carboxyl terminus.

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Abstract
The HLA-DR antigen, a complex of 2 glycoproteins of 29,000 and 34,000 daltons, can be isolated from the membranes of human B [bone marrow-derived] lymphoblastoid cell lines. Extensive proteolysis releases only 5-10% of the antigen, whereas detergent solubilizes all of it. Detergent solubilization after papain proteolysis of membranes produces antigen with chains cleaved near the carboxyl termini. Comparison of these 3 preparations demonstrated that each chain contains a carboxyl-terminal hydrophilic region that is sensitive to proteolytic degradation and a penultimate hydrophobic region, responsible for membrane binding, that is more resistant to papain. This 2 step cleavage of each chain is also observed during proteolysis of detergent-solubilized HLA-DR antigen. Both chains of HLA-DR in the membrane can be labeled with the lipophilic photoactivatable carbene reagent adamantane diazirine. This label is released from both chains during the 2nd cleavage. The H chain can be reduced and alkylated under mild conditions, and this label is also lost during the 2nd cleavage. The H chain is phosphorylated in vivo, and this label is lost upon the 1st cleavage. The carboxyl terminus of the H chain is intracellular. Both chains of HLA-DR antigens are apparently comprised of large extracellular NH2-terminal regions, small penultimate intramembranous regions and small carboxyl-terminal intracellular regions.