HUMAN EMBRYONIC, FETAL, & ADULT HBS HAVE DIFFERENT SUBUNIT INTERFACE STRENGTHS

人类胚胎、胎儿、

• 批准号: 7954105
• 负责人: JAMES M MANNING
• 金额: $ 0.24万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954105
• 关键词: Adult; Binding; Computer Retrieval of Information on Scientific Projects Database; Development; Embryo; Erythrocytes; Funding; Globin; Grant; Hemoglobin; Human; Institution; Ligands; Longevity; Manuscripts; Play; Property; Protein Dynamics; Proteins; Publishing; Research; Research Personnel; Resources; Role; Source; United States National Institutes of Health; Work; dimer; fetal; hemoglobin Gower; hemoglobin Portland; macromolecule; monomer

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The different types of naturally occurring, normal human hemoglobins vary in their tetramer-dimer subunit interface strengths (stabilities) by three orders of magnitude in the liganded (CO or oxy) state. The presence of embryonic zeta-subunits leads to an average 20-fold weakening of tetramer-dimer interfaces compared to corresponding hemoglobins containing adult alpha-subunits. The dimer-monomer interfaces of these hemoglobins differ by at least 500-fold in their strengths; such interfaces are weak if they contain zeta-subunits and exchange with added beta-subunits in the form of beta(4) (HbH) significantly faster than do those with alpha-subunits. Subunit exchange occurs at the level of the dimer, although tetramer formation reciprocally influences the amount of dimer available for exchange. Competition between subunit types occurs so that pairs of weak embryonic hemoglobins can exchange subunits to form the stronger fetal and adult hemoglobins. The dimer strengths increase in the order Hb Portland-2 (zeta(2)beta(2)) < Hb Portland-1 (zeta(2)gamma(2)) approximately equal Hb Gower-1 (zeta(2)epsilon(2)) < Hb Gower-2 (alpha(2)epsilon(2)) < HbF(1) < HbF (alpha(2)gamma(2)) < HbA(2) (alpha(2)delta(2)), i.e., from embryonic to fetal to adult types, representing maturation from weaker to stronger monomer-monomer subunit contacts. This increasing order recapitulates the developmental order in which globins are expressed (embryonic --> fetal --> adult), suggesting that the intrinsic binding properties of the subunits themselves regarding the strengths of interfaces they form with competing subunits play an important role in the dynamics of protein assemblies and networks. A manuscript describing this work has been published: Human embryonic, fetal, and adult hemoglobins have different subunit interface strengths. Correlation with lifespan in the red cell. Manning LR, Russell JE, Padovan JC, Chait BT, Popowicz A, Manning RS, Manning JM. Protein Sci. 2007 Aug;16(8):1641-58.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 不同类型的天然存在的正常人血红蛋白的四聚体-二聚体亚基界面强度（稳定性）在配体（CO 或氧）状态下相差三个数量级。与含有成人α亚基的相应血红蛋白相比，胚胎zeta亚基的存在导致四聚体-二聚体界面平均弱化20倍。这些血红蛋白的二聚体-单体界面的强度至少相差 500 倍；如果此类界面包含 zeta 亚基，并且与添加的 β 亚基以 β(4) (HbH) 形式进行交换，则其速度明显快于具有 α 亚基的界面。亚基交换发生在二聚体水平，尽管四聚体的形成相互影响可用于交换的二聚体的量。亚基类型之间会发生竞争，使得成对的弱胚胎血红蛋白可以交换亚基，形成更强的胎儿和成人血红蛋白。二聚体强度按 Hb Portland-2 (zeta(2)beta(2)) < Hb Portland-1 (zeta(2)gamma(2)) 的顺序增加，大约等于 Hb Gower-1 (zeta(2)epsilon(2)) < Hb Gower-2 (alpha(2)epsilon(2)) < HbF(1) < HbF (alpha(2)gamma(2)) < HbA(2) (alpha(2)delta(2))，即从胚胎到胎儿再到成人类型，代表从较弱到较强的单体-单体亚基接触的成熟。这种递增的顺序概括了球蛋白表达的发育顺序（胚胎→胎儿→成人），表明亚基本身的内在结合特性（关于它们与竞争亚基形成的界面的强度）在蛋白质组装和网络的动力学中发挥着重要作用。描述这项工作的手稿已经出版： 人类胚胎、胎儿和成人血红蛋白具有不同的亚基界面强度。与红细胞寿命的相关性。曼宁 LR、拉塞尔 JE、帕多万 JC、柴特 BT、波波维奇 A、曼宁 RS、曼宁 JM。蛋白质科学。 2007 年 8 月；16(8):1641-58。