5h94

Publication Abstract from PubMed

The lack of a peptide-swine leukocyte antigen class I (pSLA I) complex structure presents difficulties for the study of swine cytotoxic T lymphocyte (CTL) immunity and molecule vaccine development to eliminate important swine viral diseases, such as influenza A virus (IAV). Here, after cloning and comparing of 28 SLA I allelic genes from Chinese Heishan pigs, pSLA-3*hs0202 was crystalized and solved. The SLA-3*hs0202 binding with sbeta2m and a KMNTQFTAV (HA-KMN9) peptide from the 2009 pandemic swine H1N1 strain clearly displayed two distinct conformations with HA-KMN9 peptides in the structures, which are believed to be beneficial to stimulate a broad spectrum of CTL immune response. Notably, we found that different HA-KMN9 conformations are caused not only by the flexibility of the side chains of residues in the peptide-binding groove (PBG) but also by the skewing of alpha1 and alpha2 helixes forming the PBG. In addition, alanine scanning and CD spectra confirmed that the B, D and F pockets play critical biochemical roles in determining the peptide-binding motif of SLA-3*hs0202. Based on biochemical parameters and comparisons to similar pockets in other known major histocompatibility complex class I (MHC I) structures, the fundamental motif for SLA-3*hs0202 was determined as 'X-(M/A/R)-(N/Q/R/F)-X-X-X-X-X-(V/I)' by refolding in vitro and multiple mutant peptides. Finally, 28 SLA-3*hs0202-restricted epitope candidates were identified from important IAV strains, and two of them have been found in humans as HLA-A*0201-specific IAV epitopes. Structural and biochemical illumination of pSLA-3*hs0202 can benefit vaccine development to control IAV in swine. IMPORTANCE: We crystalized and solved the first SLA-3 structure, SLA-3*hs0202, and found that it could present the same IAV peptide with two distinct conformations. Unlike previously findings showing that variable peptide conformations are only caused by the flexibility of the side chains in the groove, the skewing of the alpha1 and alpha2 helixes is important in the different peptide conformations in SLA-3*hs0202. We also determined the fundamental motif for SLA-3*hs0202 as 'X-(M/A/R)-(N/Q/R/F)-X-X-X-X-X-(V/I)' based on a series of structural and biochemical analyses, and 28 SLA-3*hs0202-restricted epitope candidates were identified from important IAV strains. We believe our structure and analyses of pSLA-3*hs0202 can benefit vaccine development to control IAV in swine.

Structural and biochemical analyses of swine MHC class I complexes and prediction of the epitope map in important influenza A strains.,Fan S, Wu Y, Wang S, Wang Z, Jiang B, Liu Y, Liang R, Zhou W, Zhang N, Xia C J Virol. 2016 May 11. pii: JVI.00119-16. PMID:27170754^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.