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High-level intrinsic disorder explains the universality of CLIP binding to diverse MHC class II variants

Cellular & Molecular Immunology volume 15, pages 76–78 (2018)Cite this article

MHC class I and II molecules bind peptides that are either recognized as self or as foreign to the immune system via interaction with T-cell receptors. The T-cell receptor makes molecular contacts with the peptide and the MHC molecule in the region of the MHC peptide binding cleft. The MHC class I and II molecules are highly polymorphic, which presumably allows for great diversity of antigen-binding sites over the population, leading to a species that is relatively fit to withstand foreign pathogens. In MHC class I molecules, this allelic variation predicts extensive variation in the sequence of peptides able to bind MHC class I molecules, and this is indeed the case. However, in MHC class II molecules, there is an endogenous, default peptide, termed class II associated invariant peptide (CLIP) that occupies the polymorphic binding cleft of ~70% of the MHC class II molecules on the cell surface, that is, instead of these molecules binding either other self-peptides or foreign peptides. The basis for this binding universality, that is, the capacity for CLIP to bind many allelic MHC class II variants, has never been explained.

Several factors determine which peptide binds to which MHC class I or II allelic variant. For example, evidence indicates that certain MHC class I polymorphic variants can attain high-affinity binding with antigenic peptides independently of catalytic factors, whereas other polymorphic variants rely heavily on tapasin and the peptide loading complex for the highest affinity of MHC class I-peptide associations.1, 2, 3 Likewise, MHC class II polymorphic variants are essentially dependent on HLA-DM, which facilitates the removal of the invariant chain from the MHC class II molecule, thereby facilitating a successful competition by the peptide for the MHC class II peptide binding site.4

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Acknowledgements

We wish to acknowledge the support of the taxpayers of the State of Florida.

Author contributions

VNU, YNT and GB made the initial intrinsic disorder assessments. ON, SNB and MR obtained, filtered, and assessed the MHC class II epitopes for Table 1. VNU and GB wrote most of the manuscript. YNT and GB assembled the SOM.

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Authors and Affiliations

  1. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, and Immunology Program, Tampa, FL, USA

    Vladimir N Uversky, Yaping N Tu, Onyekachi Nwogu, Shanitra N Butler, Michael Ramsamooj & George Blanck

  2. H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    George Blanck

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  1. Vladimir N Uversky
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Correspondence to George Blanck.

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Uversky, V., Tu, Y., Nwogu, O. et al. High-level intrinsic disorder explains the universality of CLIP binding to diverse MHC class II variants. Cell Mol Immunol 15, 76–78 (2018). https://doi.org/10.1038/cmi.2017.45

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