Evolution, adaptation and structure-function relationships of extinct and extant mammalian hemoglobins: mechanisms of allosteric interactions and their interplay with temperature

脊椎动物血红蛋白直接将外部环境条件与细胞代谢过程联系起来，精心定制，以平衡肺部的氧气摄取及其向组织的输送。虽然所有血红蛋白的血红素基团(氧结合的位置)是相同的，但球蛋白的组成在物种之间可能有很大的差异。氨基酸组成看起来很小的变化，由于碱基与珠蛋白链的DNA替换而产生，可以对蛋白质的氧结合特性和对温度的敏感性产生深远的影响。这些变化无疑在哺乳动物占据不同栖息地的能力方面发挥了关键作用，但人们对它们的确切分子机制和进化模式知之甚少。这项申请是为了资助对灭绝和现存哺乳动物的血红蛋白的新研究，这些研究专门针对北极、半水生和地下环境中的生命，特别关注这些呼吸蛋白对温度和其他红细胞配体(二氧化碳、质子、氯离子和某些有机磷酸盐)的氧结合特性。他们说，这些研究构成了基础科学，解决了与这种具有生物重要性的分子的形式、功能和进化有关的基本问题。技术培训将使学生接触到最近开发的与呼吸蛋白的进化、表达和分析有关的技术，并传授分子生物学、遗传学和计算方面的技能，培养出高度胜任学术界和加拿大快速增长的以医学为基础的制药和生物技术部门的人才。最后，从这项研究计划中获得的见解可能在开发具有特殊工程特性的基于血红蛋白的血液替代品方面具有重要的应用前景。面对人们对通过献血传播病毒(艾滋病毒、肝炎、西尼罗河)和其他污染物的日益担忧，这项技术的出现越来越有吸引力。

Directly linking external environmental conditions with cellular metabolic processes, vertebrate hemoglobins are exquisitely tailored to balance the uptake of oxygen at the lungs and its delivery to the tissues. While the heme groups (the loci for oxygen binding) of all hemoglobins are identical, the globin composition can vary substantially between species. Seemingly small changes in the amino acid composition, resulting from base substitutions with the DNA of the globin chains, can have profound effects on the protein's oxygen-binding characteristics and sensitivity to temperature. These alterations have undoubtedly played a key role in the ability of mammals to occupy a diverse range of habitats, yet little is known regarding their precise molecular mechanisms and mode of evolution. This application is for funds to support novel research on hemoglobins from extinct and extant mammals specialized to life in arctic, semi-aquatic and subterranean environments, focusing specifically on the oxygen binding characteristics of these respiratory proteins in response to temperature and other red cell ligands (carbon dioxide, protons, chloride ions and certain organic phosphates).     These studies constitute basic science that addresses fundamental issues pertaining the form, function and evolution of this biologically important molecule. Technical training will expose students to recently developed techniques relating to the evolution, expression and analyses of respiratory proteins, and impart skills in molecular biology, genetics and computation, producing personnel highly qualified for employment in academia and Canada's rapidly growing medically based pharmaceutical and biotechnology sectors. Finally, insights gained from this research programme may have important applied perspectives in the development of hemoglobin-based blood substitutes with specially engineered properties. The advent of this technology is increasingly attractive in the face of increasing concern over the transmission of viral (HIV, hepatitis, West Nile) and other contaminants via donor blood.