PMID- 35218721
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20230416
IS  - 1096-0384 (Electronic)
IS  - 0003-9861 (Print)
IS  - 0003-9861 (Linking)
VI  - 719
DP  - 2022 Apr 15
TI  - A short HLA-DRA isoform binds the HLA-DR2 heterodimer on the outer domain of the 
      peptide-binding site.
PG  - 109156
LID - S0003-9861(22)00041-8 [pii]
LID - 10.1016/j.abb.2022.109156 [doi]
AB  - The human leukocyte antigen (HLA) locus encodes a large group of proteins 
      governing adaptive and innate immune responses. Among them, HLA class II proteins 
      form alpha/beta heterodimers on the membrane of professional antigen-presenting cells 
      (APCs), where they display both, self and pathogen-derived exogenous antigens to 
      CD4(+) T lymphocytes. We have previously shown that a shorter HLA-DRA isoform 
      (sHLA-DRA) lacking 25 amino acids can be presented onto the cell membrane via 
      binding to canonical HLA-DR2 heterodimers. Here, we employed atomistic molecular 
      dynamics simulations to decipher the binding position of sHLA-DRA and its 
      structural impact on functional regions of the HLA-DR2 molecule. We show that a 
      loop region exposed only in the short isoform (residues R69 to G83) is 
      responsible for binding to the outer domain of the HLA-DR2 peptide-binding site, 
      and experimentally validated the critical role of F76 in mediating such 
      interaction. Additionally, sHLA-DRA allosterically modifies the peptide-binding 
      pocket conformation. In summary, this study unravels key molecular mechanisms 
      underlying sHLA-DRA function, providing important insights into the role of 
      full-length proteins in structural modulation of HLA class II receptors.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Shams, Hengameh
AU  - Shams H
AD  - Weill Institute for Neurosciences, Department of Neurology, University of 
      California, San Francisco, CA, 94158, USA.
FAU - Hollenbach, Jill A
AU  - Hollenbach JA
AD  - Weill Institute for Neurosciences, Department of Neurology, University of 
      California, San Francisco, CA, 94158, USA; Department of Epidemiology and 
      Biostatistics, University of California, San Francisco, CA, 94158, USA.
FAU - Matsunaga, Atsuko
AU  - Matsunaga A
AD  - Weill Institute for Neurosciences, Department of Neurology, University of 
      California, San Francisco, CA, 94158, USA.
FAU - Mofrad, Mohammad R K
AU  - Mofrad MRK
AD  - Departments of Bioengineering and Mechanical Engineering, University of 
      California, Berkeley, CA, 94720, USA.
FAU - Oksenberg, Jorge R
AU  - Oksenberg JR
AD  - Weill Institute for Neurosciences, Department of Neurology, University of 
      California, San Francisco, CA, 94158, USA.
FAU - Didonna, Alessandro
AU  - Didonna A
AD  - Weill Institute for Neurosciences, Department of Neurology, University of 
      California, San Francisco, CA, 94158, USA; Department of Anatomy and Cell 
      Biology, East Carolina University, Greenville, NC, 27834, USA. Electronic 
      address: didonnaal21@ecu.edu.
LA  - eng
GR  - R01 NS102153/NS/NINDS NIH HHS/United States
GR  - TL1 TR001871/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220224
PL  - United States
TA  - Arch Biochem Biophys
JT  - Archives of biochemistry and biophysics
JID - 0372430
RN  - 0 (HLA-DR alpha-Chains)
RN  - 0 (HLA-DR2 Antigen)
RN  - 0 (Peptides)
RN  - 0 (Protein Isoforms)
SB  - IM
MH  - Binding Sites
MH  - HLA-DR alpha-Chains
MH  - *HLA-DR2 Antigen/chemistry/metabolism
MH  - Humans
MH  - *Peptides
MH  - Protein Isoforms/metabolism
PMC - PMC9007275
MID - NIHMS1785660
OTO - NOTNLM
OT  - Antigen presentation
OT  - Molecular dynamics
OT  - Protein-protein binding
OT  - Structural modulation
COIS- Conflict of interest The authors declare no competing interests. All the data 
      supporting the findings of this study are available from the corresponding author 
      upon reasonable request.
EDAT- 2022/02/27 06:00
MHDA- 2022/04/16 06:00
PMCR- 2023/04/15
CRDT- 2022/02/26 20:10
PHST- 2021/10/08 00:00 [received]
PHST- 2022/02/06 00:00 [revised]
PHST- 2022/02/22 00:00 [accepted]
PHST- 2022/02/27 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2022/02/26 20:10 [entrez]
PHST- 2023/04/15 00:00 [pmc-release]
AID - S0003-9861(22)00041-8 [pii]
AID - 10.1016/j.abb.2022.109156 [doi]
PST - ppublish
SO  - Arch Biochem Biophys. 2022 Apr 15;719:109156. doi: 10.1016/j.abb.2022.109156. 
      Epub 2022 Feb 24.