A KEYSTONE POSITION IS AFFECTED IN THE REPLACEMENT MUTATION FOUND IN HLA-DRB1*1211.

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A KEYSTONE POSITION IS AFFECTED IN THE REPLACEMENT MUTATION FOUND IN HLA-DRB1*1211.
Peter A. Horn MD ¹, David S. DeLuca MSc ¹ and Rainer Blasczyk MD ¹. ¹ Department of Transfusion Medicine, Hannover Medical School, Hannover, Lower Saxony, Germany .

Computational methods, which utilize crystallographic data, are available to understand and predict the significance of HLA protein polymorphism and thus elucidate the implications of exchanging single amino acids and its expected effect on peptide binding and alloreactivity based on the structural changes. We identified the novel allele DRB1*1211 which is characterized by a replacement mutation resulting in an amino acid substitution at a normally highly conserved position. Compared to DRB1*120101, to which it is closest, the new variant is characterized by a new replacement mutation (TC) at nucleotide position 126 of exon 2, resulting in the amino acid substitution PheLeu at position 47. This residue is part of pocket E of the peptide binding groove and is thus directly involved in peptide binding. The new allele, DRB1*1211, is therefore likely to differ substantially in its peptide binding repertoire and alloreactive potential from other DRB1*12 alleles. In addition, computational analysis reveals position 47s keystone functionality in the 1 domain, joining both segments of the alpha helix with the beta sheet and that this position plays a major role in the structural conformation of the binding groove. If one considers positions that if mutated will result in protein function impairment, as keystone positions or keystone residues, our computational model demonstrates that position 47 should be regarded as a keystone position.