HLA-B44 polymorphisms at position 116 of the heavy chain influence TAP complex binding via an effect on peptide occupancy.
A single residue polymorphism distinguishes HLA-B*4402(D116) from HLA-B*4405(Y116), which was suggested to allow HLA-B*4405 to acquire peptides without binding to tapasin-TAP complexes. We show that HLA-B*4405 is not inherently unable to associate with tapasin-TAP complexes. Under conditions of peptide deficiency, both allotypes bound efficiently to TAP and tapasin, and furthermore, random nonamer peptides conferred higher thermostability to HLA-B*4405 than to HLA-B*4402. Correspondingly, under conditions of peptide sufficiency, more rapid peptide-loading, dissociation from TAP complexes, and endoplasmic reticulum exit were observed for HLA-B*4405, whereas HLA-B*4402 showed greater endoplasmic reticulum retention and enhanced tapasin-TAP binding. Together, these studies suggest that position 116 HLA polymorphisms influence peptide occupancy, which in turn determines binding to tapasin and TAP. Relative to HLA-B*4405, inefficient peptide loading of HLA-B*4402 is likely to underlie its stronger tapasin dependence for cell surface expression and thermostability, and its enhanced susceptibility to pathogen interference strategies.
Thammavongsa
Vilasack
V
Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor 48109-0620, USA.
Raghuraman
Gayatri
G
Filzen
Tracy M
TM
Collins
Kathleen L
KL
Raghavan
Malini
M
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D015235:HLA-B Antigens / Q000235:genetics* / Q000378:metabolism*; D059948:HLA-B44 Antigen; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011485:Protein Binding; D018411:Spodoptera; D013696:Temperature; D013997:Time Factors
D017920:Antiporters; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; D010455:Peptides; C107762:tapasin