Oral Presentation 2014 International Biophysics Congress

Targeting of a natural killer cell receptor family by a viral immunoevasin (#10)

Richard Berry 1 , Natasha Ng 1 , Philippa Saunders 2 , Julian Vivian 1 , Jie Lin 2 , Felix Deuss 1 , Alexandra Corbett 2 , Catherine Forbes 3 , Jacqueline Widjaja 2 , Lucy Sullivan 2 , Adrian McAlister 1 , Matthew Perugini 4 , Melissa Call 5 , Anthony Scalzo 3 , Mariapia Delgi-Esposti 3 , Jerome Coudert 3 , Travis Beddoe 1 , Andrew Brooks 2 , Jamie Rossjohn 1
  1. Monash University, Clayton, VIC, Australia
  2. Department of Microbiology and Immunology, Melbourne University, Melbourne, VIC, Australia
  3. University of Western Australia, Nedlands, WA, Australia
  4. La Trobe University, Melbourne, VIC, Australia
  5. WEHI, Melbourne, VIC, Australia

Natural Killer (NK) cells play a crucial role in innate immunity, critical to the function of which is a polymorphic family of NK receptors that in rodents is encoded by the polygenic Ly49 cluster. The inhibitory members of the Ly49 family recognise major histocompatibility complex class I (MHC-I) molecules on the cell surface, whose down-regulation renders pathogen-infected cells susceptible to NK-mediated lysis. The molecular basis of activating NK receptor engagement is unclear however. The prototypical Ly49 activating receptor, Ly49H, confers resistance to murine cytomegalovirus (MCMV) infection by binding to the MCMV-encoded immunoevasion molecule, m157. We show that, despite being structurally similar to MHC-I, m157 did not ligate to the lectin-like natural killer domain (NKD) with which inhibitory Ly49 receptors bind MHC-I. Rather m157 bound to the extended helical-stalk region of Ly49H, allowing two m157 monomers to engage the Ly49H dimer. The two helical stalks of the Ly49H dimer lie centrally across the m157 platform, with each stalk interacting at discrete sites on m157. Surprisingly, the NKD of Ly49H is not required for recognition, as m157 can bind to polypeptides from the Ly49 stalk region equally well. The specificity of the interaction arises principally from  an “aromatic peg motif” within the Ly49H stalk, mutation of which abrogates binding. This motif is also present within certain inhibitory Ly49's, thereby explaining why m157 can bind both inhibitory and activating Ly49 receptors. Thus, presumably to avoid competition with MHC ligands, m157 has evolved to “tackle the legs” of the Ly49 receptor.