CCDC138 and Beta138 Modifications in Hemoglobin

Structure

The CCDC138 protein has been detected in a number of different organisms. It has various orthologs with multiple sequence alignment showing conserved regions. The most distant homolog is found in Trichoplax adhaerans. The protein contains several alpha helixes, beta sheets and coiled-coils.

The transforming growth factor beta (TGFb) signaling pathway orchestrates a wide breadth of biological processes and has been the focus of much therapeutic pursuit. Structural studies have helped to illuminate the underlying molecular mechanisms at many layers of this pathway.

Recent structural studies of activin class ligands have shown that these proteins display high flexibility. They can exist in a variety of open states with an unresolved wrist helix. They can also adopt a 'closed' state with a defined wrist helix. In addition, crystal structures have been solved for four of the seven type I receptor kinase domains, providing the first clear picture of how a ligand bound to these receptors is phosphorylated.

Stability

Hemoglobin stability studies on erythrocytes Beta138 exposed to ascorbate have revealed modifications that are reversible with time. The nature of these modifications has been determined by analyzing kinetic data and conducting long-term stability studies, including a 1-year evaluation of the effect of added ascorbate on hemoglobin.

An unstable hemoglobin with reduced oxygen affinity, Hemoglobin Brockton (beta 138 (H16) Ala----Pro), has been found in two unrelated families. This variant has the same electrophoretic mobility as Hb A on cellulose acetate agarose gel and cannot be resolved from Hb A on citrate agarose. X-ray crystallographic analysis suggests that the proline substitution at beta 138 does not disrupt critical inter- and intrasubunit hydrogen bonds and salt bridges at the beta carboxyl-terminal dipeptide site of normal hemoglobin.

Molecular Weight

The molecular weight is the sum of the atomic masses of all the atoms in the molecule. For example, water (H2O) has a molecular weight of 18 g/mole. Polymer molecular weight is usually measured by methods that depend on the colligative properties of the polymer, such as vapor phase osmometry.

The osmotic molecular weight for beta 138 is identical to Hb A. This suggests that the Brockton substitution does not disrupt the critical inter- and intrasubunit hydrogen bonds and salt bridges of the beta carboxyl-terminal dipeptide, which are essential for normal oxygen-binding properties.

The number average molecular weight is an estimate of the number of molecules with a particular length of polymer chain, and it is usually skewed. The skewed curve results from a high proportion of very short chains in the polymer, which are more difficult to break by entanglement with other chains. The number average molecular weight is often used to calculate the polydispersity, PD, of plastics. A low PD value indicates that the polymer chains are all of similar lengths, whereas a higher PD value is associated with broad distribution and different chain lengths.