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revised model for invarianthain-mediated assembly of MHClass II peptide receptors

orbert Koch1, Alexander D. McLellan2 and Jurgen Neumann1

Division of Immunobiology, Institute of Genetics, University of Bonn, Bonn, Germany

Department of Microbiology and Immunology, University of Otago, Otago, New Zealand

Opinion TRENDS in Biochemical Sciences Vol.32 No.12

The enormous number of allelic MHC class IIglycoproteins provides the immune system with a largeset of heterodimeric receptors for the binding ofpathogen-derived peptides. How do inherited allo- orisotypic subunits of MHC class II combine to producesuch a variety of functional peptide receptors? We pro-pose a new mechanism in which pairing of matchedMHC class II a- and b-subunits is coordinated by theinvariant chain chaperone. The assembly is proposed tooccur in a sequential fashion, with a matched b-chainbeing selected by the a-chain–invariant chain ‘scaffold’complex that is formed first. This sequential assembly isa prerequisite for subsequent intracellular transport ofthe a-chain–invariant chain–b-oligomer and its matu-ration into a functional peptide receptor.

Inherited polymorphisms result in novelprotein–protein interactionsIt is estimated that �60 000 single nucleotide polymorph-isms of the human genome are contained within genes [1].This diversity generates a large number of genes that occurin several alleles. Due to the random combination ofparental alleles in every generation of offspring, poly-morphic gene products are essentially expressed in a novelenvironment. In molecular terms, this means that thefunctional life span of a polymorphic protein is accom-panied by numerous novel interactions with otherproteins. An extremely variable region of the genome,the MHC region, is an example of a highly regulatedassembly of polymorphic proteins [2]. The MHC class II(MHCII) region encodes a great variety of proteins thatserve the immune system by presenting antigenic peptidesto CD4+ helper T cells [3]. Evolutionary selection pressureby pathogenic microorganisms has ensured that MHCIIgenes display an extremely high level of polymorphism. [4].To date, more than 870 MHCII allotypes have been ident-ified in the human population (European BioinformaticsInstitute; www.ebi.ac.uk), from which �600 proteins wereexpressed. This high polymorphism produces a great diver-sity of peptide receptors and enables the species to surveyan amazing variety of peptide sequences derived from themultitude of pathogenic organisms.

Corresponding author: Koch, N. (norbert.koch@uni-bonn.de).Available online 5 November 2007.

ww.sciencedirect.com 0968-0004/$ – see front matter � 2007 Elsevier Ltd. All rights reserve

The polymorphic MHCII a- and b-subunits combinewith the non-polymorphic invariant chain (Ii) to form apremature peptide receptor. The present model of MHCIIsubunit assembly suggests that a- and b-chains form aheterodimer, which binds to the trimer of Ii [5]. This model,however, does not explain how mismatched pairing, whichmight occur between some of the polymorphic a- andb-chains, is prevented. Here, we introduce a revised conceptof how the enormous variety of MHCII subunits is matchedby interaction with Ii to form functional peptide receptors.

Isotypic and haplotypic pairing of MHCII moleculesThe human MHC consists of two regions, one containingthe class I A, B and C genes and one containing the class IID genes. The class II region is divided into three subregionsthat encode a- and b-subunits of the DP, DQ and DRisotypes (note, in the mouse H2 region, two class II sub-regions encode a- and b-subunits of isotypes I-A and I-E; Idenotes ‘immune response genes’). The duplication ofgenes, resulting in MHCII isotypes, has created additionaldiversity to the codominantly expressed alleles, at the levelof individuals. In the sequence of MHCII, most polymorph-isms are concentrated in the first domain of b-chains. DPand DQ a-chains show some moderate allelic variations atthe N-terminus of the a1 domain, whereas the DRa-encod-ing gene exhibits unremarkable genetic diversity. Themouse orthologs for DR (I-E) and DQ (I-A) exhibit a com-parable polymorphism.

The MHCII ab heterodimers present antigens (whichhave been harvested in endocytic compartments and deliv-ered to the cell surface) for recognition by CD4+ T cells.During antigen loading, the cohort of MHCII receptorsbinds to a large array of peptides that contain certainmotifs. An antigenic sequence of eight to ten amino acidresidues contained within a peptide of 13 to 18 residues inlength is lodged in a groove formed by the association ofMHCII a- and b-glycoproteins. One to four (anchor) resi-dues of the peptide sequence enable binding of the peptideinto the polymorphic pockets of the b-sheet of the MHCIIgroove. The peptide-binding groove protects the core pep-tide from further proteolysis.

MHCII a-subunits show a distinct preference forcombining with their matched isotype b-subunit (i.e.DQa prefers to combine with DQb). However, in trans-fected cells, some of the MHCII isotype subunits might

d. doi:10.1016/j.tibs.2007.09.007

Opinion TRENDS in Biochemical Sciences Vol.32 No.12 533

combine to give rise to mixed heterodimeric complexes,creating a genetically unpredicted diversity [6], but it isunclear whether the mixed isotype complexes exist undernormal conditions within the cell. Expression of mixedisotype combinations of the MHCII peptide receptorswould be expected to increase the repertoire of antigenspresented by a single antigen-presenting cell (APC). How-ever, this is not necessarily the case because formation ofmisfolded MHCII complexes by aberrant association ofsubunits could severely impair antigen presentation.Furthermore, inter-isotypic MHCII pairing in humanAPCs would strongly reduce the amount of the less abun-dantly expressed DP and DQ molecules (compared withDR) and possibly abolish the unique role of these twoisotypes. Thus, regulation of matched isotype a- and b-chain pairing could be required to ensure optimal immuneresponsiveness (Figure 1).

Similar to isotype matching, allotypic class II subunitpairs have to be examined to determine if they match toform peptide receptors. Allotypic MHCII variants differ intheir assembly efficiency. For assembly of some allotypiccombinations, coexpression of Ii is strictly required,whereas other combinations assemble efficiently even ifexpression of Ii is omitted [7]. Mouse H2-A a- and b-chainsthat are encoded on a single chromosome seem to beevolutionarily selected for heterodimer formation [8].Mixed haplotype pairing occurs when a- and b-chains ofthe same isotype, but encoded from genes expressed on theallelic chromosome, combine to form functional units. Ininbred mouse strains, these combinations of polymorphicMHCII subunits are not found on parental cells and areunique in APCs from F1 hybrid mice. Indeed, in mice it hasbeen shown that H2-A subunits encoded by some mixedhaplotypes show an absolute dependence on the Ii chaper-one for optimal folding and transport of the resultantheterodimer [8].

The chaperone role of li in MHCII subunit assemblyUpon biosynthesis, proteins are translocated into theendoplasmic reticulum (ER) and there pass a quality

Figure 1. A model for matched isotype MHCII subunit assembly. MHCII isotypes derive

subunits to MHCII peptide receptors is regulated in an APC yielding matched intra-isotyp

expressed on the cell surface as peptide receptors (middle arrow). (a) DR, DP and DQ a-

chain, Ii (yellow), with matched isotype DP, DQ and DR b-chains (green, red and blue

pairing. Following the maturation of MHCII oligomers, Ii is degraded, and the Ii-derived

absence of Ii, the a- and b-isotype subunits form mixed complexes. The fate of the mixe

the formation of matched isotype heterodimers, which are exposed as peptide recepto

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control system that involves interaction with chaperones.Most known ER-resident chaperones transiently bind to awide array of proteins, which appear after translation.Discrete transport competent multiprotein complexesare formed upon selective folding and assembly of proteinsubunits. Newly synthesized MHCII glycoproteins passthrough a transiently aggregated phase [9,10]. These aber-rantly mixed MHCII subunits are temporarily complexedwith chaperones, such as the ER-resident membraneprotein calnexin, or the soluble immunoglobulin heavychain binding protein (BiP) and possibly other, not yetdefined, chaperones [11–13]. Immediately following theaggregated phase, Ii binds to theMHCII chains, promotingfolding and subsequent export of the class II complex out ofthe ER [14]. An additional role of Ii is to sort MHCIImolecules into endocytic compartments, where Ii isdegraded. An MHCII-attached fragment of Ii, class II-associated Ii peptide (CLIP), is released upon interactionwith the class II-like DM molecules [HLA-DM (human),H2-DM (mouse)] and replaced by antigenic peptide [15].Although Ii is essential for the optimal expression of sur-face MHCII, a- and b-chains can form dimers in theabsence of Ii [9]. For example, in vitro translated a- andb-chains form dimers in the presence of microsomes, whichare essential for the assembly of the MHCII membrane-bound subunits [16]. Therefore, it was suggested that apreformed a–b heterodimer binds to Ii [16,17]. Because aninteraction of Ii with individual MHCII subunits has alsobeen reported [18–20], this issue remained controversial.Although Ii is not required for the presentation of allantigens [21], the absence of Ii often causes defectiveMHCII export [22] and aberrant association of DM withMHCII subunits in the ER (DM catalyses the acquisition ofpeptides by the MHCII heterodimer) [23]. Ii-dependency ofMHCII function is explained by the role of Ii to promote theassembly of MHCII subunits and by targeting the MHCII–Ii complex to peptide-loading compartments.

The Ii chain occupies the MHCII groove andprevents the binding of proteins that appear after biosyn-thesis in the ER. In MHCII-transfected Ii-free cells, newly

from duplicated genes, which encode a- and b-chains. Assembly of the a- and b-

e, rather than inter-isotype, combinations. The matched isotypes are subsequently

chains (green, red and blue, respectively) assemble in the presence of the invariant

, respectively) to form functional peptide receptors. Ii regulates matched isotype

fragment CLIP (grey) is replaced by an antigenic peptide (light brown). (b) In the

d-isotype MHCII heterodimers is unclear. The excess of DR subunits might result in

rs on the cell surface.

534 Opinion TRENDS in Biochemical Sciences Vol.32 No.12

synthesized MHCII molecules are not significantly loadedwith peptide but associate with misfolded polypeptides inthe ER [24]. Presumably, the loading conditions in the ERare not optimal for MHCII peptide binding [25].

Ii binds to the enormous number of polymorphic class IIglycoproteins without any reported exception. Interactionof Ii with the MHC isotypes DP, DQ and DR is strong,whereas binding to the nonclassical MHCII molecules DMand DO and to the class Ib molecule CD1d can only bedetected in lysates using mild detergent [26,27]

Conserved Ii-binding sites on MHCII chainsThree Ii chains form a trimer [28], to which MHCIIsubunits are attached. The multicomponent frameworkof the MHCII–Ii structure suggests several interactionsites [29]. It has been reported that the transmembranedomains of MHCII and Ii are capable of self-association[30]. However, this interaction is only stable in mild deter-gent and is complemented by association of other parts ofthe molecules [31,32]. Ii utilizes a sequence encompassingresidues 91 to 99 to bind to the groove of MHCII peptidereceptors. The peptide backbone of this Ii sequence pro-vides an additional promiscuous binding site to conservedamino acid residues in the peptide-binding groove ofMHCII heterodimers [33].

Interaction of Ii with distinct non-polymorphicsequences onMHCII subunits is required for the promiscu-ous binding of Ii to the large family ofMHCII glycoproteins.Individual MHCII a-chains efficiently coisolate with Ii,whereas individual b-chains exhibit only a low-affinityinteraction with Ii [34]. Ii residues Met91, Ala94 andMet99 bind to pockets 1, 4 and 9 of the MHCII (DR3allotype) groove [33]. The first pocket (P1) is predominantlyformed by conserved DRa residues (Figure 2a). A

Figure 2. Conserved MHCII binding sites for li. Two binding sites of Ii to conserved sequ

of Ii residue Met91 to DRa. The second binding site is located on DRb. Binding of a prolin

the MHCII–Ii complex. (a) Pocket 1 of the DR3–CLIP complex with residues Phe32 and Trp

(grey ribbon). In this figure, DRa is depicted as a ribbon, and DRb is depicted as a backbo

the page. In this view, it is DRb that is depicted as the ribbon, and DRa as a backbone

structure to demonstrate a potential interaction of Ii residues with Trp153, Tyr123 and

structures are depicted as green and coils are grey [Protein Database (PDB) accession

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Met91->Gly mutant (which is the anchor for P1) of Iicompletely abolished co-isolation of Ii with individualDRa chains [34]. This result suggests that Ii is dockedto conserved residues of DRa. Binding of the a-subunit to Iimight suggest interaction with non-polymorphic residues,which explains the promiscuous binding of Ii to all MHCIIallo- and isotypes. It is important that the single b-chaindoes not bind efficiently to Ii because the largemolar excessof Ii, which is expressed in APCs, would impair assembly ofa–Ii–b complexes and preferentially produce a–Ii and b–Iipairs. The detection of a preformed a–Ii complex suggests asequential binding of a- and b-subunits to the Ii trimer. Bymetabolic labelling experiments, it was demonstrated thatthe a-chain attaches to Ii within 5 minutes [34]. This a–Iiscaffold subsequently binds to the b-subunit. Consistentwith this finding, a–b dimer intermediates were notobserved [5].

How does the a–Ii complex promiscuously interact withmatched MHCII b-chains? The extra-cytoplasmic part ofDRb consists of a highly polymorphic b1 and a moreconserved b2 domain. One study identified a novel motifin the sequence of the DRb chain, which is defined by twotryptophan residues separated by 22 amino acids [35]. This‘WW MHC class II’ (WWCII) sequence is conserved in theMHCIIb2 domains of vertebrate species. In the DRb chain,Trp153 and Tyr123, which are located within the WWCIIsequence, form a pocket-like structure and, in conjunctionwith Asp152, mediate interaction with a proline-richregion of Ii found adjacent to the groove-binding sequenceof Ii (Figure 2b).

Editing of matched MHCII subunits by liUnlike MHC-I, MHCII heterodimers do not acquirepeptides in the ER. Therefore, at the stage of assembly,

ences of DRa and DRb chains are depicted. One of the binding sites directs docking

e-rich sequence of Ii to this WWCII sequence on DRb accomplishes the formation of

43 (both yellow) of DRa binds to Met91 (light-brown) of the Ii-derived fragment CLIP

ne. (b) The same complex rotated 90 degrees anticlockwise relative to the plane of

. Lys83 and Pro82 (light brown) at the N-terminus of CLIP were modelled into this

Asp152 of the DRb chain (all yellow). Turns between b-sheets or between a- to b-

1A6A]. Data from [33].

Figure 3. Models for the assembly of MHCII subunits with Ii. A single APC expresses up to 11 a- and b-subunits of various allo- and isotypes. The model presented here, in

contrast to the opposed ‘classic model’, might explain how functional peptide receptors are selected out of the various transiently generated a- and b-associates. (a) The

various MHCII b-chains expressed in an APC are capable of transiently binding to the a–Ii scaffold. Allo- and isotypic b-chains then compete for binding to a–Ii. Ii edits

transiently expressed a–Ii–b complexes for matched a–b heterodimers. Subsequently, matched MHCII heterodimers exit the ER and travel to class II peptide-loading

compartments. (b) Two models for MHCII subunit assembly. (i) The ‘classic’ model: a preformed a–b heterodimer is inserted into a loop formed by the Ii trimer (the segment

of Ii that generates CLIP is labelled in grey). (ii) Our new ‘revised’ model: an Ii trimer first binds to the MHCII a-chain. Subsequently, the b-chain associates with the matrix (or

‘scaffold’) formed by a–Ii, and it is at this stage that the isotype is checked as a match for the a-subunit.

Opinion TRENDS in Biochemical Sciences Vol.32 No.12 535

the a- and b-subunits are not examined by antigenicpeptides to form functional peptide receptors. Based onnovel data [34,35], we propose a new model for MHCIIsubunit assemblywhereby theMHCIIa–Ii complex forms ascaffold to which a matched b-glycoprotein is selectivelybound (Figure 3a). The a–Ii matrix can bind to any MHCIIb-chain. However, in the presence of the isotype-matchedb-subunit, a transport-competent a–Ii–b oligomer isformed. This a–Ii–b complex is qualified to mature intoa a–b peptide receptor.

Within the transient a–Ii–b complex, the b-chain isexamined as a potential subunit of the MHCII peptidereceptor complex. The groove-binding sequence of Ii hasthe role of a master peptide. Interaction of some poly-morphic residues of the MHCII b-chain with the Ii masterpeptide sequence and with the a1 domain might test theability of the b-chain to fit into the complex. The poly-morphic residues of the MHCII b-chain might determinethe conversion of transient to stable MHCII complexes. Inaddition, a recently described hydrogen bond between theconserved His81 of the b-chain and a carbonyl group of thepeptide backbone stabilizes the complex [36]. If interactionof the b-chain to the master sequence is inefficient, it isreplaced by one of the various MHCII b-chains expressedin APCs. Interaction of the b-chain with a–Ii is accom-plished by binding of a proline-rich region of Ii to WWCIIon the b-chain. A WWCII mutant of the DRb chain thatstill binds to Ii and to DRa was transported intracellularly

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and subsequently expressed on the cell surface [35]. In thepresence of wild-type DRb, however, association of theWWCII mutant to DRa and Ii was abolished. It was there-fore suggested that the chaperone role of Ii is regulated byinteraction of Ii with theWWCII domain on the DRb chain.

The conformation of the MHCII peptide receptor isinfluenced by its interaction with Ii. A conformationalchange of the a–b heterodimer, observed in the presenceof Ii, is maintained following Ii degradation in endosomesand MHCII expression on the cell surface [37]. The struc-ture of the a–Ii–b complex could be different from a com-plex that would be produced by preformed a–b thatassociates with the Ii trimer [Figure 3b(i)]. The ‘classic’model suggests that a–b heterodimers are required toinsert into a loop contained in the Ii trimer [38]. By con-trast, our revised model suggests that the a- and b-chainsform a sandwich-like structure with the Ii trimer[Figure 3b(ii)]. An advantage of this sandwich model isthat a mismatched b-chain can still dissociate from the a–Ii matrix and be replaced by amatched b-chain. In contrastto a–Ii–b [Figure 3b(ii)], an exchange of the b-chain in thea–b–Ii complex [Figure 3b(i)] containing preformed a–b

dimers requires several steps of dissociation and reassoci-ation.

Concluding remarksIn contrast to the previously described model (outlinedin Figure 3), our new model suggests that Ii is required

536 Opinion TRENDS in Biochemical Sciences Vol.32 No.12

to select polymorphic b-chains in the formation ofpeptide-binding units. Given the numerous a- and b-allo-types encoded by the human genome, not all a–b dimerswill form functional peptide receptors. This is particularlyimportant for DQ and DP subunits because both a- andb-chains of these isotypes are polymorphic. A novel com-bination of polymorphic MHCII a- and b-subunits in everyoffspring needs to be examined as a functional peptide-binding unit. The ‘classic’ model of a preformed a–b het-erodimer does not explain how matching subunits areefficiently selected out of the various MHCII glycoproteinsexpressed in a given APC. The requirement for selectiveassembly is evident when one considers the number ofpotential combinations of isotype subunits and the result-ing intra-isotype heterodimers [39].We suggest that in thisselection process, Ii functions as a unique chaperone forMHCII isotype subunit assembly. Ii promotes the for-mation of DR, DP and DQ a–b heterodimers and detersinter-isotypic MHCII pairing. At present, there is no evi-dence for MHCII peptide receptors other than DR, DP orDQ heterodimers. It is, however, conceivable that, out ofthe great variety of MHCII molecules, some mixed isotypea–b heterodimers are assembled, which form functionalpeptide receptors.

Matched or aberrantly assembled MHCII subunits canbe distinguished by their ability (or inability) to enter theMHCII processing pathway. It is still unclear which struc-tural requirement enables export of the MHCII moleculesfrom the ER.

An additional question concerns the stoichiometry ofMHCII oligomers. Are there several MHCII isotypes con-tained in one complex with the Ii trimer? For mouseMHCII, it has been demonstrated that I-A and I-E hetero-dimers form distinct complexes with Ii [40,41]. This ques-tion has not been resolved for human MHCII isotypes.

AcknowledgementsThis work has been supported by a grant from the DeutscheForschungsgemeinschaft.

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