Distinct Differences in Structural States of Conserved Histidines in Two Related Proteins: NMR Studies of the Chemokines CXCL1 and CXCL8 in the Free Form and Macromolecular Complexes

Biochemistry
Krishna Mohan Sepuru, Krishna Rajarathnam

Abstract

Hydrogen-bonding and ionic interactions play fundamental roles in macromolecular recognition and function. In contrast to lysines and arginines, how histidines mediate these interactions is less well-understood due to the unique properties of its side chain imidazole that include an aromatic ring with two titratable nitrogens, a p Ka that can vary significantly, and the ability to exist in three distinct forms: protonated imidazolium and two tautomeric neutral (Nδ1 and Nε2) states. Here, we characterized the structural features of histidines in the chemokines CXCL8 and CXCL1 in the free, GAG heparin-bound, and CXCR2 receptor N-terminal domain-bound states using solution NMR spectroscopy. CXCL8 and CXCL1 share two conserved histidines, one in the N-loop and the other in the 30s loop. In CXCL8, both histidines exist in the Nε2 tautomeric state in the free, GAG-bound, and receptor-bound forms. On the other hand, in unliganded CXCL1, each of the two histidines exists in two states, as the neutral Nε2 tautomer and charged imidazolium. Further, both histidines exclusively exist as the imidazolium in the GAG-bound and as the Nε2 tautomer in the receptor-bound forms. The N-loop histidine alone in both chemokines is involved in direct G...Continue Reading

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Citations

Aug 29, 2019·The Journal of Biological Chemistry·Krishna Mohan Sepuru, Krishna Rajarathnam
Dec 22, 2020·IScience·Krishna Mohan SepuruKrishna Rajarathnam

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