TAPBPR promotes antigen loading on MHC-I molecules using a peptide trap.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
    • Publication Information:
      Original Publication: [London] : Nature Pub. Group
    • Subject Terms:
      Antigen Presentation*; Histocompatibility Antigens Class I/*metabolism ; Immunoglobulins/*metabolism ; Membrane Proteins/*metabolism ; Molecular Chaperones/*metabolism; Antigens/metabolism ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Gene Knockout Techniques ; HEK293 Cells ; Histocompatibility Antigens Class I/genetics ; Histocompatibility Antigens Class I/isolation & purification ; Histocompatibility Antigens Class I/ultrastructure ; Humans ; Immunoglobulins/genetics ; Immunoglobulins/isolation & purification ; Immunoglobulins/ultrastructure ; Ligands ; Membrane Proteins/genetics ; Membrane Proteins/isolation & purification ; Membrane Proteins/ultrastructure ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism ; Molecular Chaperones/genetics ; Molecular Chaperones/ultrastructure ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Mutation ; Peptide Library ; Protein Binding/genetics ; Protein Binding/immunology ; Recombinant Proteins/genetics ; Recombinant Proteins/isolation & purification ; Recombinant Proteins/metabolism ; Recombinant Proteins/ultrastructure
    • Abstract:
      Chaperones Tapasin and TAP-binding protein related (TAPBPR) perform the important functions of stabilizing nascent MHC-I molecules (chaperoning) and selecting high-affinity peptides in the MHC-I groove (editing). While X-ray and cryo-EM snapshots of MHC-I in complex with TAPBPR and Tapasin, respectively, have provided important insights into the peptide-deficient MHC-I groove structure, the molecular mechanism through which these chaperones influence the selection of specific amino acid sequences remains incompletely characterized. Based on structural and functional data, a loop sequence of variable lengths has been proposed to stabilize empty MHC-I molecules through direct interactions with the floor of the groove. Using deep mutagenesis on two complementary expression systems, we find that important residues for the Tapasin/TAPBPR chaperoning activity are located on a large scaffolding surface, excluding the loop. Conversely, loop mutations influence TAPBPR interactions with properly conformed MHC-I molecules, relevant for peptide editing. Detailed biophysical characterization by solution NMR, ITC and FP-based assays shows that the loop hovers above the MHC-I groove to promote the capture of incoming peptides. Our results suggest that the longer loop of TAPBPR lowers the affinity requirements for peptide selection to facilitate peptide loading under conditions and subcellular compartments of reduced ligand concentration, and to prevent disassembly of high-affinity peptide-MHC-I complexes that are transiently interrogated by TAPBPR during editing.
    • References:
      Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E1006-15. (PMID: 26869717)
      Tissue Antigens. 2015 Mar;85(3):155-66. (PMID: 25720504)
      J Immunol. 2016 Feb 15;196(4):1480-7. (PMID: 26783342)
      Mol Immunol. 2019 Sep;113:58-66. (PMID: 30077416)
      J Biol Chem. 2015 Jan 30;290(5):2593-603. (PMID: 25505266)
      Nucleic Acids Res. 2011 Jan;39(Database issue):D913-9. (PMID: 21062830)
      Oncoimmunology. 2017 Jan 3;6(2):e1274476. (PMID: 28344889)
      Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20597-20606. (PMID: 32788370)
      Cell Rep. 2019 Nov 5;29(6):1621-1632.e3. (PMID: 31693900)
      Elife. 2018 Nov 28;7:. (PMID: 30484775)
      J Mol Biol. 2007 Oct 19;373(2):503-19. (PMID: 17825317)
      Annu Rev Immunol. 2015;33:169-200. (PMID: 25493333)
      J Immunol. 2007 Jun 15;178(12):7890-901. (PMID: 17548627)
      J Comput Chem. 1999 Jun;20(8):786-798. (PMID: 35619462)
      Elife. 2017 Apr 20;6:. (PMID: 28425917)
      Curr Opin Immunol. 2017 Jun;46:97-102. (PMID: 28528220)
      Prog Nucl Magn Reson Spectrosc. 2020 Feb;116:56-84. (PMID: 32130959)
      J Immunol. 2006 Nov 15;177(10):7015-23. (PMID: 17082617)
      Nature. 2017 Nov 23;551(7681):525-528. (PMID: 29107940)
      Bioinformatics. 2015 Apr 15;31(8):1325-7. (PMID: 25505092)
      Bioinformatics. 2014 Oct 15;30(20):2968-70. (PMID: 24990609)
      Nat Protoc. 2006;1(3):1120-32. (PMID: 17406393)
      Elife. 2020 Mar 13;9:. (PMID: 32167472)
      Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):5055-5060. (PMID: 30808808)
      Bioinformatics. 2011 Dec 15;27(24):3430-1. (PMID: 22006916)
      Methods Enzymol. 2011;487:545-74. (PMID: 21187238)
      Mol Cell Biol. 2008 Jun;28(12):4040-51. (PMID: 18426917)
      J Cell Sci. 2014 Jul 1;127(Pt 13):2885-97. (PMID: 24806963)
      Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25602-25613. (PMID: 31796585)
      Eur J Immunol. 2012 Jun;42(6):1405-16. (PMID: 22678897)
      Int J Cancer. 2005 Feb 10;113(4):611-8. (PMID: 15455354)
      F1000Res. 2017 Feb 17;6:158. (PMID: 28299193)
      Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3429-33. (PMID: 1565634)
      J Immunol. 2000 Jun 15;164(12):6398-405. (PMID: 10843695)
      Elife. 2015 Oct 06;4:. (PMID: 26439010)
      BMC Bioinformatics. 2013 Dec 01;14:346. (PMID: 24289175)
      Science. 2017 Nov 24;358(6366):1060-1064. (PMID: 29025996)
      J Biomol NMR. 1995 Nov;6(3):277-93. (PMID: 8520220)
      Nat Methods. 2009 Aug;6(8):551-2. (PMID: 19644455)
      J Immunol. 1998 Jan 1;160(1):77-86. (PMID: 9551958)
      J Biol Chem. 2005 Jun 24;280(25):23900-9. (PMID: 15849183)
      J Mol Biol. 2013 Sep 23;425(18):3563-75. (PMID: 23827138)
      Annu Rev Immunol. 2013;31:443-73. (PMID: 23298205)
      Science. 2017 Nov 24;358(6366):1064-1068. (PMID: 29025991)
      Front Immunol. 2019 May 03;10:966. (PMID: 31130956)
      J Immunol. 2015 Nov 1;195(9):4503-13. (PMID: 26416272)
      J Biol Chem. 2019 Mar 29;294(13):4759-4774. (PMID: 30723160)
      Protein Eng Des Sel. 2019 Dec 31;32(12):525-532. (PMID: 32725167)
      J Chem Theory Comput. 2015 Mar 10;11(3):1308-14. (PMID: 26579776)
      Immunity. 2004 Jan;20(1):71-85. (PMID: 14738766)
      J Biomol NMR. 2016 Dec;66(4):259-271. (PMID: 27878649)
      Mol Cell. 2011 Apr 22;42(2):250-60. (PMID: 21458342)
      Nat Chem Biol. 2018 Aug;14(8):811-820. (PMID: 29988068)
      Sci Rep. 2015 Nov 27;5:17341. (PMID: 26611325)
      Science. 2013 Feb 15;339(6121):823-6. (PMID: 23287722)
      Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4956-61. (PMID: 21383159)
      Nat Commun. 2020 Mar 11;11(1):1314. (PMID: 32161266)
      Science. 2011 May 13;332(6031):816-21. (PMID: 21566186)
      Structure. 2013 Oct 8;21(10):1735-42. (PMID: 24035711)
    • Grant Information:
      R01 AI143997 United States AI NIAID NIH HHS; R35 GM125034 United States GM NIGMS NIH HHS; S10 OD018455 United States OD NIH HHS
    • Accession Number:
      0 (Antigens)
      0 (Histocompatibility Antigens Class I)
      0 (Immunoglobulins)
      0 (Ligands)
      0 (Membrane Proteins)
      0 (Membrane Transport Proteins)
      0 (Molecular Chaperones)
      0 (Peptide Library)
      0 (Recombinant Proteins)
      0 (TAPBPL protein, human)
      0 (tapasin)
    • Publication Date:
      Date Created: 20210527 Date Completed: 20210609 Latest Revision: 20240402
    • Publication Date:
      20240402
    • Accession Number:
      PMC8154891
    • Accession Number:
      10.1038/s41467-021-23225-6
    • Accession Number:
      34039964