Analysis of human α globin gene mutations that impair binding to the α hemoglobin stabilizing protein
Year: 2009
Type: article
Abstract: Alpha hemoglobin stabilizing protein (AHSP) reversibly binds nascent alpha globin to maintain its native structure and facilitate its incorporation into hemoglobin A. Previous studies indicate that some naturally occurring human alpha globin mutations may destabilize the protein by inhibiting its interactions with AHSP. However, these mutations could also affect hemoglobin A production through AHSP-independent effects, including reduced binding to beta globin. We analyzed 6 human alpha globin variants with altered AHSP contact surfaces. Alpha globin amino acid substitutions H103Y, H103R, F117S, and P119S impaired interactions with both AHSP and beta globin. These mutations are destabilizing in biochemical assays and are associated with microcytosis and anemia in humans. By contrast, K99E and K99N alpha globins bind beta globin normally but exhibit attenuated binding to AHSP. These mutations impair protein folding and expression in vitro and appear to be mildly destabilizing in vivo. In Escherichia coli and erythroid cells, alpha globin K99E stability is rescued on coexpression with AHSP mutants in which binding to the abnormal globin chain is restored. Our results better define the biochemical properties of some alpha globin variants and support the hypothesis that AHSP promotes alpha globin chain stability during human erythropoiesis.
Source: Blood
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G2154546777, Biotechnology Research Training Grant, G3591803973, G4931488477, Functional Properties of Hemoglobins and Myoglobins, The Role of Alpha Hemoglobin Stabilizing Protein in Human Beta Thalassemia, Trim58 and the Ubiquitin Proteasome System in Erythro-megakaryopoiesis, The function and regulation of alpha hemoglobin stabilizing protein (AHSP) in hem, Design of Heme Protein-Based Blood Substitutes, G7792105565, G8209665308, Rutgers Center for Environmental Exposure and Disease (CEED)
OpenAlex ID: W2012618006