Regulation of MHC class I heterodimer stability and interaction with TAP by tapasin.
Major histocompatibility complex (MHC) class I molecules are heterodimers of a class I heavy chain and beta 2-microglobulin that bind peptides supplied by the MHC region-encoded transporters associated with antigen processing (TAP). Peptide binding by class I heterodimers is necessary for their maturation into stable complexes and is dependent on their physical association with TAP. In human mutant 721.220 cells, however, a novel genetic defect causes the failure of class I heterodimers to associate with TAP. This deficiency correlates with lack of expression of a glycoprotein, tapasin (TAP-associated glycoprotein), which has been found in association with class I heterodimers and TAP. Employing a transcomplementation analysis, we obtained evidence co-localizing the genetic defect of mutant 220 cells and the structural or a regulatory gene controlling the expression of tapasin on the short arm of chromosome 6, which includes the MHC. Expression of tapasin and the normal interaction of class I heterodimers with TAP are concomitantly restored, indicating the probable function of tapasin as a physical link between these complexes. In further support of this model, the absence of tapasin in mutant 220 cells correlates with reduced class I heterodimer stability, suggesting that tapasin may stabilize class I heterodimers and thereby enhance their association with TAP. These results further implicate tapasin in a mechanism that promotes peptide binding by class I heterodimers through their interaction with TAP.
Grandea
A G
AG
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA 98104, USA.
Lehner
P J
PJ
Cresswell
P
P
Spies
T
T
D017920:Antiporters / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002896:Chromosomes, Human, Pair 6; D019281:Dimerization; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D026901:Membrane Transport Proteins
D017920:Antiporters; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D007136:Immunoglobulins; D026901:Membrane Transport Proteins; C107762:tapasin