Genetics of the Immune System | Neuronal Signaling Mechanisms | Cell Signaling & Trafficking Structures | Neuromuscular Diseases
Peptide mimics of the torpedo and human AChR main immunogenic regions
Robert H Fairclough*, Vu B Trinh, Nelson A Page
*Corresponding author: Robert H Fairclough
Department of Neurology, University of California, Davis School of Medicine, Davis, CA, USA
F1000Posters 2012, 3: 579 (poster) [English]
Poster [662.44 KB]
New York Academy of Sciences 2012 - 12th International Conference on Myasthenia Gravis and Related Disorders , 21 - 23 May 2012, P000
We have synthesized a 39 amino acid peptide mimic of the conformation dependent Torpedo AChR main immunogenic region (MIR) to study this important target of the Abs in experimental autoimmune myasthenia gravis (EAMG) and human myasthenia gravis (MG): alpha(1-12)GGGS (65-79)GS(110-115). The mimic is expressed as a fusion protein at the N-terminus of an intein chitin-binding domain and adsorbed to chitin beads. We have studied this complex to assess how well it mimics the MIR of the Torpedo AChR and the human AChR since mAb 132A binds to both of these receptors.
mAb 132A binds to the mimic and to the Torpedo AChR with quite similar dissociation constants (Kds). However, when the 39 amino acid mimic is mutated to the corresponding sequences for the human receptor, mAb 132A does not bind to that construct. Mutating only K115H and R79H produces a chimeric human/Torpedo mimic that binds 132A with a Kd ten times smaller than the Kd for the 132A/Torpedo mimic! Amazingly the human/Torpedo chimeric mimic peptide exhibits a very stable structure following 3 nsec of temperature equilibration in a molecular dynamics simulation, whereas the Torpedo and rat sequences show several highly mobile regions after the 3 nsec equilibration.
We are working to develop the human peptide mimic that clears the anti-MIR component of human MG serum.
No relevant competing interests disclosed.
MG Alliance of New York, none
MG Foundation of California, none
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