NMR spectroscopy reveals unexpected structural variation at the protein–protein interface in MHC class I molecules

Beerbaum, Monika; Ballaschk, Martin; Erdmann, Natalja; Schnick, Christina; Diehl, Anne; Uchańska-Ziegler, Barbara; Ziegler, Andreas; Schmieder, Peter

doi:10.1007/s10858-013-9777-z

Cited by 40 publications

(35 citation statements)

References 63 publications

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“…Given that binding of peptide and b 2 m to the heavy chain are cooperative Elliott et al, 1991), it is mechanistically consistent that the C84-C139 disulfide bond also increases the b 2 m binding affinity of K b . As we see no significant differences between wild-type K b and K b -Y84C in the crystal structure positions of the residues at the interface of the heavy chain with b 2 m (Shields et al, 1999;Achour et al, 2002;Achour et al, 2006;Hee et al, 2012), we propose that the coupling between peptide binding and b 2 m binding occurs through the conformational dynamics of the heavy chain Beerbaum et al, 2013;Bailey et al, 2014). Further investigation of K b -Y84C might elucidate this coupling, which is central to MHC-I stability and to the molecular understanding of cellular peptide selection.…”

Section: Discussionmentioning

confidence: 55%

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control*

Hein

Uchtenhagen

Abualrous

et al. 2014

Journal of Cell Science

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The intracellular trafficking of major histocompatibility complex class I (MHC-I) proteins is directed by three quality control mechanisms that test for their structural integrity, which is correlated to the binding of high-affinity antigenic peptide ligands. To investigate which molecular features of MHC-I these quality control mechanisms detect, we have followed the hypothesis that suboptimally loaded MHC-I molecules are characterized by their conformational mobility in the F-pocket region of the peptide-binding site. We have created a novel variant of an MHC-I protein, K b -Y84C, in which two a-helices in this region are linked by a disulfide bond that mimics the conformational and dynamic effects of bound highaffinity peptide. K b -Y84C shows a remarkable increase in the binding affinity to its light chain, beta-2 microglobulin (b 2 m), and bypasses all three cellular quality control steps. Our data demonstrate (1) that coupling between peptide and b 2 m binding to the MHC-I heavy chain is mediated by conformational dynamics; (2) that the folded conformation of MHC-I, supported by b 2 m, plays a decisive role in passing the ER-to-cell-surface transport quality controls; and (3) that b 2 m association is also tested by the cell surface quality control that leads to MHC-I endocytosis.

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Section: Discussionmentioning

confidence: 55%

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control*

Hein

Uchtenhagen

Abualrous

et al. 2014

Journal of Cell Science

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“…Thirdly, the differences in MHC I plasticity and corresponding selector function have been shown here for three HLA-B molecules, and the generality of this observation remains to be explored, in particular by considering additional HLA alleles and point mutations. However, there is in vitro and computational evidence suggesting that plasticity is a common functional property of MHC I192022244546 and many other proteins3647.…”

Section: Discussionmentioning

confidence: 99%

Selector function of MHC I molecules is determined by protein plasticity

Bailey

Dalchau

Carter

et al. 2015

Sci Rep

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The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity, and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and α3 domain of MHC I allosterically, resulting in enhanced peptide selector function.

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“…Another study also showed that β 2 m seems to sense allelic as well as peptide-induced conformational variations and accommodates to them, showing a high degree of plasticity within the inter-domain interface with the HC domains (110). NMR-chemical-shift changes of complexes were most pronounced in the region close to the F-pocket.…”

Section: Dynamic Features Of Peptide-bound Mhc Complexesmentioning

confidence: 99%

Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation

Abualrous²,

et al. 2017

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Antigen presentation by major histocompatibility complex (MHC) proteins is essential for adaptive immunity. Prior to presentation, peptides need to be generated from proteins that are either produced by the cell’s own translational machinery or that are funneled into the endo-lysosomal vesicular system. The prolonged interaction between a T cell receptor and specific pMHC complexes, after an extensive search process in secondary lymphatic organs, eventually triggers T cells to proliferate and to mount a specific cellular immune response. Once processed, the peptide repertoire presented by MHC proteins largely depends on structural features of the binding groove of each particular MHC allelic variant. Additionally, two peptide editors—tapasin for class I and HLA-DM for class II—contribute to the shaping of the presented peptidome by favoring the binding of high-affinity antigens. Although there is a vast amount of biochemical and structural information, the mechanism of the catalyzed peptide exchange for MHC class I and class II proteins still remains controversial, and it is not well understood why certain MHC allelic variants are more susceptible to peptide editing than others. Recent studies predict a high impact of protein intermediate states on MHC allele-specific peptide presentation, which implies a profound influence of MHC dynamics on the phenomenon of immunodominance and the development of autoimmune diseases. Here, we review the recent literature that describe MHC class I and II dynamics from a theoretical and experimental point of view and we highlight the similarities between MHC class I and class II dynamics despite the distinct functions they fulfill in adaptive immunity.

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NMR spectroscopy reveals unexpected structural variation at the protein–protein interface in MHC class I molecules

Cited by 40 publications

References 63 publications

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control*

Peptide-independent stabilization of MHC class I molecules breaches cellular quality control*

Selector function of MHC I molecules is determined by protein plasticity

Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation

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