Structural evidence for an unblocked VHI sub-subgroup of human heavy chains

The N-terminal amino acid sequence of an unblocked human heavy chain of an IgGK paraprotein from patient Tho is reported. This unblocked VH sequence belongs to the VHI subgroup and has striking structural homology to an unblocked VHI sequence previously reported for the IgGK paraprotein isolated from the serum of patient Bro. Direct sequence comparison of the Tho and Bro proteins reveals complete structural identity in 25 of the N-terminal 27 residues, with unique amino acid substitutions shared at the N-terminus and positions 16, 18, and 24. This remarkable sequence homology suggests that the two VH sequences represent examples of an unblocked VHI sub-subgroup. The Tho and Bro sequences possess an ala-glu-val basic triplet at positions 9 to 11 in common with the other previously reported VHI proteins which help to further establish this sequence triplet as a recognizable VHI subgroup-specific region. Moreover, in this regard, the unblocked sequences of Tho and Bro emphasize the importance of extending an unblocked VHI sequence beyond positions 9 to 11 before a subgroup assignment can be determined.