Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function

Gary K. Ackers, Paula M. Dalessio, George H. Lew, Margaret A. Daugherty, Jo M. Holt

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

The mechanism of cooperativity in the human hemoglobin tetramer (a dimer of αβ dimers) has historically been modeled as a simple two-state system in which a low-affinity structural form (T) switches, on ligation, to a high-affinity form (R), yielding a net loss of hydrogen bonds and salt bridges in the dimer-dimer interface. Modifications that weaken these cross-dimer contacts destabilize the quaternary T tetramer, leading to decreased cooperativity and enhanced ligand affinity, as demonstrated in many studies on symmetric double modifications, i.e., a residue site modified in both α- or both β-subunits. In this work, hybrid tetramers have been prepared with only one modified residue, yielding molecules composed of a wild-type dimer and a modified dimer. It is observed that the cooperative free energy of ligation to the modified dimer is perturbed to the same extent whether in the hybrid tetramer or in the doubly modified tetramer. The cooperative free energy of ligation to the wild-type dimer is unperturbed, even in the hybrid tetramer, and despite the overall destabilization of the T tetramer by the modification. This asymmetric response by the two dimers within the same tetramer shows that loss of dimer-dimer contacts is not communicated across the dimer-dimer interface, but is transmitted through the dimer that bears the modified residue. These observations are interpreted in terms of a previously proposed dimer-based model of cooperativity with an additional quaternary (T/R) component.

Original languageEnglish (US)
Pages (from-to)9777-9782
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number15
DOIs
StatePublished - Jul 23 2002

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'Single residue modification of only one dimer within the hemoglobin tetramer reveals autonomous dimer function'. Together they form a unique fingerprint.

Cite this