Structural Understanding of Beta138

 

Structure

The transforming growth factor beta (TGFb) signaling pathway orchestrates multiple biological processes from bone development to fertility. It is currently the subject of intense therapeutic pursuits. Structural biology studies have provided foundational knowledge of this large-scale and multifaceted pathway from a molecular perspective, but there remain gaps in our structural understanding at several layers of the pathway.

Multiple structures of activin class ligands have been resolved in both the open state with an unstable wrist helix (GDF11, GDF8, and antibody bound-GDF8) as well as the classic state (Apo-GDF11, ActRIIB-Alk5:GDF11, and Fs288:GDF11). Hemoglobin Brockton [beta 138 (H16) Ala----Pro] is an unstable hemoglobin variant that exhibits reduced intrinsic oxygen affinity but otherwise has similar electrophoretic mobility and hemolysate polar interactions to Hb A. The increased instability of this hemoglobin variant correlates with the absence of a buried hydrogen bond formed between Pro 138 beta and Asp 134 beta in the helix. The presence of this critical salt bridge is essential for the cooperative oxygenation process in hemoglobin.

Function

The beta function is a special integral Slot138 with many applications in Physics and string theory. It is also known as the incomplete beta function or Euler’s beta function B(p, q).

For two integers a and b in the domain of positive real numbers, the incomplete beta function can be expressed as a polynomial of degree a + b - 1 with rational coefficients. It is also a function of two variables that can be used in statistical analysis (for example, as a normalizing constant in the probability density functions for the F and Student’s t distribution).

Hemoglobin Brockton [beta 138 (H16) Ala----Pro] has low oxygen affinity but electrophoretic mobility and hemolysate binding are normal, suggesting that the substitution at beta 138 does not disrupt important polar interactions, such as the hydrogen bonds and salt bridges between Asp 137 and Pro 138, that contribute to the cooperative oxygen-binding process in Hb A. The variant is unstable and has been associated with mild anemia.

Diagnosis

Patients with beta138 typically present with enduring slate-gray cyanosis at birth or in early infancy, often with elevated Hb and a right-shift of the O2Hb curve. These findings, together with methemoglobinemia, suggest the presence of an unstable hemoglobin variant. Molecular studies confirm the presence of the unstable hemoglobin variant, usually Hemoglobin Bristol-Alesha (HBB 67 Val-Met-->Asp; classical numbering), also known as hemoglobin ala138pro, or Hemoglobin Sydney (Hb E11(67)Val-->Met). Patients with hemoglobin Bristol-Alesha can develop extreme hemolysis with variable severity and have a thalassemic hyperunstable hemoglobinopathy with an extremely short lifespan. Hemoglobin Bristol-Alesha is caused by a GTG to ATG mutation at codon 67 of the HBB gene, resulting in an alanine to proline substitution at position 138 of the mature beta globin chain.