Distinct binding sites on HLA-DR for invariant chain and staphylococcal enterotoxins.

Karp, David R.; Jenkins, R N; Long, Eric O.

doi:10.1073/pnas.89.20.9657

Cited by 18 publications

(9 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the relatively small size of the Ii trimerization domain (compared with the class II structure), and the likelihood that Ii and TSST‐1 class II‐binding sites overlap (Karp et al ., 1992; Romagnoli and Germain, 1994), three HLA‐DR molecules forming a symmetric complex with Ii 118‐192 would probably, for steric reasons, contact lateral sites on the Ii domain. Figure 4 presents a rough but plausible model of such a complex, taking Ii sequence conservation, Ii/enterotoxin class II‐binding competition and geometric constraints into account.…”

Section: Resultsmentioning

confidence: 99%

Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii

Jasanoff

Wagner

Wiley

1998

EMBO J

View full text Add to dashboard Cite

The invariant chain (Ii) plays a critical role in MHC class II antigen processing by stabilizing peptide-free class II alphabeta heterodimers in a nonameric (alphabetaIi)3 complex soon after their synthesis and directing transport of the complex from the endoplasmic reticulum to compartments where peptide loading of class II takes place. Loading progresses following Ii proteolysis and via an intermediate complex of MHC class II with an Ii-derived peptide, CLIP. CLIP is substituted by exogenous peptidic fragments in an exchange reaction catalyzed by HLA-DM. The CLIP region of Ii, roughly residues 81-104, is one of two segments shown to interact with class II HLA-DR molecules. The other segment, Ii 118-216, is C-terminal to CLIP, mediates trimerization of the ectodomain of Ii and interferes with DM/class II binding. Here we report the three-dimensional structure of this trimeric domain, determined by nuclear magnetic resonance (NMR) studies of a 27 kDa trimer of human Ii 118-192. The cylindrical shape of the molecule and the mapping of conserved residues delimit surfaces which may be important for interactions between Ii and class II molecules.

show abstract

Section: Resultsmentioning

confidence: 99%

Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii

Jasanoff

Wagner

Wiley

1998

EMBO J

View full text Add to dashboard Cite

show abstract

“…The contributions of Ii lumenal subregions to class II heterodimer export from the ER and to inhibition of peptide binding were examined using constructs lacking the endosomal localization signals in residues 2-19 of the Ii cytoplasmic tail (22,23,29,30). Class II molecules expressed in cells lacking Ii show retention in the ER (10,20,23,24) and poor acquisition of endo H resistant N-linked glycans (5,(7)(8)(9)(10).…”

Section: Resultsmentioning

confidence: 99%

The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy.

Romagnoli

Germain

1994

The Journal of Experimental Medicine

180

133

View full text Add to dashboard Cite

SummaryInvariant chain (Ii) contributes in a number of distinct ways to the proper functioning of major histocompatibility complex (MHC) class II molecules. These include promoting effective association and folding of newly synthesized MHC class II c~ and B subunits, increasing transit of assembled heterodimers out of the endoplasmic reticulum (ER), inhibiting class II peptide binding, and facilitating class II movement to or accumulation in endosomes/lysosomes. Although the cytoplasmic tail of Ii makes a key contribution to the endocytic localization of class II, the relationship between the structure of Ii and its other diverse functions remains unknown. We show here that two thirds of the lumenal segment of Ii can be eliminated without affecting its contributions to the secretory pathway events of class II folding, ElK to Golgi transport, or inhibition of peptide binding. These same experiments reveal that a short (25 residue) contiguous internal segment of Ii (the CLIP region), frequently found associated with purified MHC class II molecules, is critical for all three functions. Together with other recent findings, these results raise the possibility that the contributions of Ii to the early postsynthetic behavior of class II may depend on its interaction with the class II binding site. This would be consistent with the intracellular behavior of unoccupied MHC class I and class II molecules as incompletely folded proteins and imply a related structural basis for the similar contributions of Ii to class II and of short peptides to class I assembly and transport.U 'pon synthesis and translocation into the endoplasmic reticulum (ER) 1, the component chains of class I and class II MHC molecules need to acquire a transport-competent conformation for effective post-ER transport. To achieve proper folding and a stable heavy chain-B2 microglobulin interaction suitable for secretory pathway transit, MHC class I molecules require binding site occupancy with short peptides primarily generated in the cytosol and imported into the ER via TAP (1-3). In contrast, MHC class II molecules assemble as a stoichiometric complex with trimers of the type II integral membrane glycoprotein invariant chain (Ii) (4). In the secretory pathway, this association with Ii has effects on the properties of class II analogous to those resulting from peptide interaction with class I (3). Thus, interaction with intact Ii contributes to efficient, stable association of the class II c~ and j8 subunits in the ER (5, 6), promotes the transport of class II oe/~8 heterodimers from the ER through the Golgi complex (5, 7-10), and inhibits the binding of other ligands (peptides) to the class II molecules (11-13). Whether these multiple effects of Ii require the entire molecule or are medi1Abbreviations used in this paper: endo H, endoglycosidase H; ER, endoplasmic reticulum; Ii, invariant chain. ated by one or more structurally independent subregions of the protein is presently unknown. A particularly intriguing question is whether the effects of Ii on ...

show abstract

“…Peripheral T cells stimulated with monoclonal antibodies directed against specific V,3 proteins in the presence of IL-2 produced at least a twofold increase in the amount of the appropriate V# PCR product even though there was no detectable increase in the number of cells in culture (data not shown), demonstrating that increased amounts of mRNA resulting from activation of VA3-specific T cells could be detected. In addition, proliferation driven by Vf3-specific superantigens resulted in a marked increase of the appropriate V13 PCR product (41 ). Finally, addition of small numbers of monoclonal T cell populations (5%) to T cells derived from the peripheral blood of a normal donor was easily detected (data not shown).…”

Section: Introductionmentioning

confidence: 89%

T cell receptor V beta gene bias in rheumatoid arthritis.

Jenkins

Nikaein²,

Zimmermann³

et al. 1993

J. Clin. Invest.

Self Cite

115

View full text Add to dashboard Cite

Polymerase chain reaction (PCR) technology was employed to examine peripheral blood and synovial T increased synovial expression of V/i14 was found, but only in the synovial fluid samples. Reduced expression of V#1, Vj64, V/i5.1, V/i10, V,816, and V/i19 was also observed in synovial T cells. These results indicate that biased V,8 gene utilization in different peripheral compartments of RA patients can be observed in unselected T cell populations, and are consistent with the conclusion that populations of T cells expressing these V/i gene products may be involved in the pathogenesis of the disease. (J. Clin. Invest. 1993. 92:2688-2701

show abstract

Distinct binding sites on HLA-DR for invariant chain and staphylococcal enterotoxins.

Abstract: During biosynthesis, class I molecules of the major histocompatibility complex exist as complexes of the polymorphic a and ( chains in association with trimers of the invariant chain (Ii). The

Cited by 18 publications

References 35 publications

Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii

Structure of a trimeric domain of the MHC class II-associated chaperonin and targeting protein Ii

The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy.

T cell receptor V beta gene bias in rheumatoid arthritis.

Contact Info

Product

Resources

About