Dynamics of Allostery in Hemoglobin: Roles of the Penultimate Tyrosine H bonds

Kneipp, Janina; Balakrishnan, Gurusamy; Chen, Ruopian; Shen, Tong-Jian; Sahu, Sarata C.; Ho, Nancy T.; Giovannelli, Janel L.; Simplăceanu, Virgil; Ho, Chien; Spiro, Thomas G.

doi:10.1016/j.jmb.2005.11.006

Cited by 36 publications

(31 citation statements)

References 71 publications

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“…also been previously observed in myoglobin (9, 10) and human tetrameric hemoglobin (11). Principal component analysis (PCA) (12) also validates that the clamshell motion is the dominant motion (Fig.…”

Section: Resultssupporting

confidence: 81%

Cooperative macromolecular device revealed by meta-analysis of static and time-resolved structures

Ren

Šrajer

Knapp

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Here we present a meta-analysis of a large collection of static structures of a protein in the Protein Data Bank in order to extract the progression of structural events during protein function. We apply this strategy to the homodimeric hemoglobin HbI from Scapharca inaequivalvis. We derive a simple dynamic model describing how binding of the first ligand in one of the two chemically identical subunits facilitates a second binding event in the other partner subunit. The results of our ultrafast time-resolved crystallographic studies support this model. We demonstrate that HbI functions like a homodimeric mechanical device, such as pliers or scissors. Ligandinduced motion originating in one subunit is transmitted to the other via conserved pivot points, where the E and F′ helices from two partner subunits are "bolted" together to form a stable dimer interface permitting slight relative rotation but preventing sliding.allostery | cooperativity | structural dynamics | time-resolved crystallography H emoglobins are molecular oxygen transporters in vertebrates and many invertebrates. Although the variety of quaternary assemblies of hemoglobins (1, 2) suggests considerable diversity in the strategies to achieve cooperativity, a general hypothesis remains valid: A newly ligated subunit communicates with its unligated partners via conformational changes, either tertiary or quaternary, thereby altering the ligand affinity of its partner subunits (3-5). However, the key question remains obscure: How are ligand-induced structural changes that originate in one subunit transmitted to the other to structurally modulate its ligand binding affinity? This paper harnesses structural evidence presently embedded in a large number of static and time-resolved structures of HbI and presents a simple cooperative mechanism. We take advantage of noncrystallographic symmetry (NCS) as a unique opportunity to examine asymmetric, but cooperative, behavior between subunits in different structural environments imposed by crystal lattices (6) (Fig. S1). The main finding of this study is summarized by an animated cartoon (Movie S1) showing our proposed cooperative mechanical model in action.Unlike mammalian hemoglobins, the interface of HbI homodimer consists of a longer and straight helix E and a bent helix F from each subunit (1, 7). These two helices hold a heme group in between (Figs. 1A and 2A). Each heme group is anchored to the proximal His101 located near the end of helix F. In this paper, we refer to the two subunits as A and B and the two helices in one subunit as E and F. The notations E′ and F′ refer to E and F in the partner subunit. ResultsHere we propose a simple mechanical model to explain the mechanism of cooperative change in ligand binding affinity in homodimeric HbI (Fig. 1A and Movies S1 and S2). In this model, motions transmit from one subunit to the other via two pairs of "bolted" helices E-F′ and E′-F at the dimer interface so that the majority of the intersubunit contacts remain undisturbed during transition between allo...

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Section: Resultssupporting

confidence: 81%

Cooperative macromolecular device revealed by meta-analysis of static and time-resolved structures

Ren

Šrajer

Knapp

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Anaemia has many different causes, although iron deficiency is the most common cause. As absence of iron decreases heme synthesis, hypochromic red blood cells (lacking the red hemoglobin pigment) and microcytic red blood cells (smaller than normal) (Kneipp et al, 2006).…”

Section: Assessment Of Nutritional Status Using Packed Cell Volume Anmentioning

confidence: 99%

Assessing the nutritional status of beef cattle: current practices and future prospects

Ndlovu¹,

Chimonyo²,

Okoh³

et al. 2007

Afr. J. Biotechnol.

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Accurate determination of nutritional and health status of animals is invaluable in modern animal agriculture. Body weights and body condition scoring are the commonly used methods of assessing nutritional status of animals. This paper discusses drawbacks these methods have and highlights the benefits for using blood metabolites in assessing nutritional status of beef cattle. Blood metabolite levels indicate the extent of metabolism of energy, proteins and other nutrients in animals. Glucose, cholesterol, non-esterified fatty acids, protein, urea, creatinine, albumin, globulin, minerals, liver enzymes and haematology can be used objectively, reliably and routinely to assess the nutritional status of cattle. In Southern Africa, the use of these metabolites is rare due to lack of equipment for blood analysis and the high cost of analyzing the blood parameters. However, use of high value Nguni cattle in Southern Africa requires the use of blood parameters to accurately assess their nutritional status. Several factors, such as physiological status of an animal, breed, nutrition, season and age affect levels of blood metabolites. Combining body weights, body condition scores and blood metabolites increase accuracy of assessing the nutritional state and welfare of beef cattle.

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“…In the case of positive co-operativity, both models are valid, and Model 2 based on assumption (2.2) may prove better in modelling other aspects of co-operativity. Such models can prove better at explaining experimental data other than saturation curves (see, e.g., Changeux and Edelstein, 1998;Eaton et al, 1999Eaton et al, , 2007Bruno et al, 2001;Henry et al, 2002;Kneipp et al, 2006;Popovych et al, 2006). For k ¼ 1 (the affinities of all binding sites of the (macro) molecule towards the ligand molecules being the same irrespective of conformational transitions or ligand binding, or w ¼ x) and any fixed n41, however, both Eqs.…”

Section: Comparing Models 1 Andmentioning

confidence: 99%

Minimal models of multi-site ligand-binding kinetics

Juška

2008

Journal of Theoretical Biology

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Dynamics of Allostery in Hemoglobin: Roles of the Penultimate Tyrosine H bonds

Cited by 36 publications

References 71 publications

Cooperative macromolecular device revealed by meta-analysis of static and time-resolved structures

Cooperative macromolecular device revealed by meta-analysis of static and time-resolved structures

Assessing the nutritional status of beef cattle: current practices and future prospects

Minimal models of multi-site ligand-binding kinetics

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