PMID- 17573425
OWN - NLM
STAT- MEDLINE
DCOM- 20071211
LR  - 20231105
IS  - 0006-3495 (Print)
IS  - 1542-0086 (Electronic)
IS  - 0006-3495 (Linking)
VI  - 93
IP  - 8
DP  - 2007 Oct 15
TI  - Natural MHC class I polymorphism controls the pathway of peptide dissociation 
      from HLA-B27 complexes.
PG  - 2743-55
AB  - Analysis of antigen dissociation provides insight into peptide presentation modes 
      of folded human leukocyte antigen (HLA) molecules, which consist of a heavy 
      chain, beta2-microglobulin (beta2m), and an antigenic peptide. Here we have 
      monitored peptide-HLA interactions and peptide dissociation kinetics of two 
      HLA-B27 subtypes by fluorescence depolarization techniques. A single natural 
      amino-acid substitution distinguishes the HLA-B*2705 subtype that is associated 
      with the autoimmune disease ankylosing spondylitis from the 
      non-disease-associated HLA-B*2709 subtype. Peptides with C-terminal Arg or Lys 
      represent 27% of the natural B*2705 ligands. Our results show that dissociation 
      of a model peptide with a C-terminal Lys (GRFAAAIAK) follows a two-step 
      mechanism. Final peptide release occurs in the second step for both HLA-B27 
      subtypes. However, thermodynamics and kinetics of peptide-HLA interactions reveal 
      different molecular mechanisms underlying the first step, as indicated by 
      different activation energies of 95+/-8 kJ/mol (HLA-B*2705) and 150+/-10 kJ/mol 
      (HLA-B*2709). In HLA-B*2709, partial peptide dissociation probably precedes fast 
      final peptide release, while in HLA-B*2705 an allosteric mechanism based on 
      long-range interactions between beta2m and the peptide binding groove controls 
      the first step. The resulting peptide presentation mode lasts for days at 
      physiological temperature, and determines the peptide-HLA-B*2705 conformation, 
      which is recognized by cellular ligands such as T-cell receptors.
FAU - Winkler, Kathrin
AU  - Winkler K
AD  - Physics Department, Freie Universitat Berlin, Berlin, Germany.
FAU - Winter, Anja
AU  - Winter A
FAU - Rueckert, Christine
AU  - Rueckert C
FAU - Uchanska-Ziegler, Barbara
AU  - Uchanska-Ziegler B
FAU - Alexiev, Ulrike
AU  - Alexiev U
LA  - eng
PT  - Journal Article
DEP - 20070615
PL  - United States
TA  - Biophys J
JT  - Biophysical journal
JID - 0370626
RN  - 0 (HLA-B27 Antigen)
RN  - 0 (Peptides)
SB  - IM
MH  - Binding Sites
MH  - Computer Simulation
MH  - *Genes, MHC Class I
MH  - HLA-B27 Antigen/*chemistry/*ultrastructure
MH  - Humans
MH  - *Models, Chemical
MH  - *Models, Molecular
MH  - Peptides/*chemistry
MH  - Protein Binding
MH  - Structure-Activity Relationship
PMC - PMC1989716
EDAT- 2007/06/19 09:00
MHDA- 2007/12/12 09:00
PMCR- 2008/10/15
CRDT- 2007/06/19 09:00
PHST- 2007/06/19 09:00 [pubmed]
PHST- 2007/12/12 09:00 [medline]
PHST- 2007/06/19 09:00 [entrez]
PHST- 2008/10/15 00:00 [pmc-release]
AID - S0006-3495(07)71528-X [pii]
AID - 96602 [pii]
AID - 10.1529/biophysj.106.096602 [doi]
PST - ppublish
SO  - Biophys J. 2007 Oct 15;93(8):2743-55. doi: 10.1529/biophysj.106.096602. Epub 2007 
      Jun 15.