Evolutionary and functional insights into the mechanism underlying body-size-related adaptation of mammalian hemoglobin.

Olga Rapp,Ofer Yifrach

doi:10.7554/elife.47640

Abstract

Hemoglobin (Hb) represents a model protein to study molecular adaptation in vertebrates. Although both affinity and cooperativity of oxygen binding to Hb affect tissue oxygen delivery, only the former was thought to determine molecular adaptations of Hb. Here, we suggest that Hb affinity and cooperativity reflect evolutionary and physiological adaptions that optimized tissue oxygen delivery. To test this hypothesis, we derived the relationship between the Hill coefficient and the relative affinity and conformational changes parameters of the Monod-Wymann-Changeux allosteric model and graphed the 'biophysical Hill landscape' describing this relation. We found that mammalian Hb cooperativity values all reside on a ridge of maximum cooperativity along this landscape that allows for both gross- and fine-tuning of tissue oxygen unloading to meet the distinct metabolic requirements of mammalian tissues for oxygen. Our findings reveal the mechanism underlying body size-related adaptation of mammalian Hb. The generality and implications of our findings are discussed.

Highlights

Two major obstacles hamper understanding the evolutionary origins of properties seen in modernday proteins
We emphasized the need to consider the property of Hb cooperativity, along with p50, in addressing molecular adaptation of Hb in mammals
We formulated the explicit mathematical dependences of the nH and p50 macroscopic Hb parameters on the elementary microscopic parameters of the MWC model, providing a quantitative framework to understand the mechanism underlying the adaptive behavior of these two parameters with respect to tissue oxygen delivery

Summary

Introduction

Two major obstacles hamper understanding the evolutionary origins of properties seen in modernday proteins. One stems from the fact that mutation and selection are separated by several levels of biological organization such that it is difficult to elucidate the complex relationships between protein sequence and organismal/population fitness Even in those cases where the molecular properties of a protein (e.g. affinity or cooperativity) have adaptive value with respect to organismal fitness, we often lack an understanding of the molecular mechanism underlying changes in the values of these properties. Hb is a tetrameric allosteric protein responsible for tissue oxygen delivery in a manner controlled by the midpoint and slope of its oxygen saturation curve These macroscopic parameters reflect the effective affinity (p50) and cooperativity (nH) of oxygen binding by Hb, respectively and are traditionally evaluated using the Hill equation, derived assuming an all-or-none mode of binding (Hill, 1910). Vertebrates native to mountain habitats where low ambient oxygen pressures

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