Protein structure in the truncated (2/2) hemoglobin family

Abstract

The discovery of protein sequences belonging to the widespread 'truncated hemoglobin' family has been followed in the last few years by extensive analyses of their three‐dimensional structures. Truncated hemoglobins can be classified in three main groups, in light of their overall structural properties. The three groups adopt a 2‐on‐2 α‐helical sandwich fold, based on four main α‐helices of the classical 3‐on‐3 α‐helical sandwich found in vertebrate and invertebrate globins. Each of the three groups displays sequence and structure specific features. Among these, a protein matrix tunnel system is typical of group I, a Trp residue at the G8 topological site is conserved in groups II and III, and residue TyrB10 is almost invariant in the three groups. Despite sequence variability in the heme distal site region, a strongly intertwined, but varied, network of hydrogen bonds stabilizes the heme ligand in the three protein groups. Fine mechanisms of ligand recognition and stabilization may vary based on group‐specific distal site residues and on differing ligand diffusion pathways to the heme. Taken together, the structural considerations here presented underline that 'truncated hemoglobins' result from careful editing of the 3‐on‐3 α‐helical globin sandwich fold, rather than from simple 'truncation' events. Thus, '2/2Hb' appears the most proper term to concisely address this protein family.

Ligand migration in the truncated hemoglobin of Mycobacterium tuberculosis

“…These residues play major roles in the ligand pathways (9,16,18,19). Different residues may determine which ligand will be bound or modulate the rate of binding and diffusion (19). In Mt-trHbN, two conformations of Y(B10) and Q(E11) side chains within the hydrogen-bond network were observed, depending on the presence or absence of O 2 (20)(21)(22).…”

“…In Bacillus subtilis (Bs)-trHbO, Y(B10) has been identified to be the residue directly hydrogen bonded to the ligand, while Y(CD1) is the corresponding residue in Mt-trHbO (19). Several tunnels and cavities have been identified in trHbOs (9,16,18,19). Residues lining the tunnels are hydrophobic and are conserved throughout each trHb family.…”

“…Both the association and dissociation rates of O 2 were dramatically increased in the W(G8)F mutant, whereas only the association rate increased significantly in the Y(CD1)F mutant (16). In Bacillus subtilis (Bs)-trHbO, Y(B10) has been identified to be the residue directly hydrogen bonded to the ligand, while Y(CD1) is the corresponding residue in Mt-trHbO (19). Several tunnels and cavities have been identified in trHbOs (9,16,18,19).…”

“…There is a change in the orientation of W(G8) in Mt-trHbO between the deoxy and the oxy or carbonmonoxy structures (9). The W(G8) may also play a key role in stabilizing the heme group and thus modulating the rate of ligand escape (9,16,19). Kinetic studies of the W(G8)F and Y(CD1)F proteins have demonstrated that specific residues affect ligand kinetics in different ways.…”

“…Residues lining the tunnels are hydrophobic and are conserved throughout each trHb family. These residues play major roles in the ligand pathways (9,16,18,19). Different residues may determine which ligand will be bound or modulate the rate of binding and diffusion (19).…”