Ann Taylor/Hemoglobin: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Ann Taylor

@@ Line 2: / Line 2: @@
 '''Hemoglobin''' is an oxygen-transport protein.  Hemoglobin is an [[allosteric protein]].  It is a tetramer composed of two types of subunits designated α and β, with stoichiometry <scene name='Hemoglobin/Alpha2beta2/7'>α2β2</scene>. The <scene name='Hemoglobin/Foursubunits/5'>four subunits</scene> of hemoglobin sit roughly at the corners of a tetrahedron, facing each other across a <scene name='57/576710/Cavity/1'>cavity</scene> at the center of the molecule. Each of the subunits <scene name='Hemoglobin/Bbsubunitswithheme/5'>contains a heme</scene> prosthetic group. The <scene name='Hemoglobin/4heme/3'>heme molecules</scene> give hemoglobin its red color.
-The α and β subunits have very similar structures, despite their sequence differences. We will use a single <scene name='57/576710/A_subunit_rainbow/1'>α chain</scene>  to examine the subunit structure more closely.  The 6 major and 2 short α-helices that make up the structure of a Hb subunit (the "globin fold") are <scene name='57/576710/A_subunit_labelled_helices/1'>labeled A through H</scene>, which is the traditional naming scheme. The helices form an approximately-cylindrical bundle, with the heme and its central Fe atom bound in a <scene name='57/576710/Hydrophobic_pocket/1'>hydrophobic pocket</scene> (hydrophobic = grey; hydrophilic = purple).  The proximal histidine (the tightest protein-Fe intraction) is often called <scene name='57/576710/His_f9/2'>His F9</scene>, since it is residue 9 on helix F (it is residue 87 in the human α chain).   A second histidine is near the bound oxygen, and is referred to as the <scene name='57/576710/Distal_his/2'>distal histidine</scene>. In the deoxy state, the Fe2+ is <scene name='57/576710/Deoxy_non_planarity/1'>below the plane</scene> of the porphyrin ring.  When oxygen is bound, the iron changes spin state, resulting in the iron moving <scene name='57/576710/Oxy_fe_planarity/2'>into the plane</scene> of the heme.
+The α and β subunits have very similar structures, despite their sequence differences. We will use a single <scene name='57/576710/A_subunit_rainbow/1'>α chain</scene>  to examine the subunit structure more closely.  The 6 major and 2 short α-helices that make up the structure of a Hb subunit (the "globin fold") are <scene name='57/576710/A_subunit_labelled_helices/1'>labeled A through H</scene>, which is the traditional naming scheme. The helices form an approximately-cylindrical bundle, with the heme and its central Fe atom bound in a <scene name='57/576710/Hydrophobic_pocket/1'>hydrophobic pocket</scene> (hydrophobic = grey; hydrophilic = purple).  The proximal histidine (the tightest protein-Fe intraction) is often called <scene name='57/576710/His_f9/2'>His F9</scene>, since it is residue 9 on helix F (it is residue 87 in the human α chain).   A second histidine is near the bound oxygen, and is referred to as the <scene name='57/576710/Distal_his/3'>distal histidine</scene>. In the deoxy state, the Fe2+ is <scene name='57/576710/Deoxy_non_planarity/2'>below the plane</scene> of the porphyrin ring.  When oxygen is bound, the iron changes spin state, resulting in the iron moving <scene name='57/576710/Oxy_fe_planarity/3'>into the plane</scene> of the heme.
 <scene name='32/32/Cv/2'>This animation scene</scene> made by ''Alexander Berchansky'' shows the <span style="color:pink;background-color:black;font-weight:bold;">oxy (in pink)</span> and <span style="color:deepskyblue;background-color:black;font-weight:bold;">deoxy (in deepskyblue)</span> α1 heme groups were superimposed on each other, to give a local comparison at this site, a closeup around the heme O2-binding site.  The heme is quite domed in the <span style="color:deepskyblue;background-color:black;font-weight:bold;">deepskyblue T-state (deoxy) form</span>, with the 5-coordinate, high-spin <span style="color:orange;background-color:black;font-weight:bold;">Fe (orange ball)</span> out of the plane.  In the <span style="color:pink;background-color:black;font-weight:bold;">pink R-state form</span> a CO molecule is bound at the right <span style="color:lime;background-color:black;font-weight:bold;">(C in green</span>,<font color='red'><b>O in red</b></font>); the Fe, now 6-coordinate low-spin, has moved into the heme plane, which has flattenened.  The proximal His (at left) connects the Fe to helices on the proximal side, making the Fe position sensitive to changes in the globin structure and vice versa.  Remember that this scene shows a subunit in the all-unliganded versus the all-liganded states of Hb; when oxygen binds to just one subunit, then its internal structure undergoes some but not all of these changes, depending on conditions.   <jmol><jmolButton>
@@ Line 13: / Line 13: @@
 ==T to R transition==
-For hemoglobin to function as an oxygen-carrier in the blood, it must have an equilibrium between the two main states of its quaternary structure, the unliganded "deoxy" or "T state" versus the liganded "oxy" or "R state".  The unliganded (deoxy) form is called the "T" (for "tense") state because it contains extra stabilizing interactions between the subunits, specifically <scene name='57/576710/Deoxy_salt_bridges/1'>ionic interactions</scene>.  In the high oxygen affinity R-state conformation, these ionic interactions <scene name='57/576710/Oxy_ionic_interactions/1'>are lost</scene>, and the tetramer is described as "relaxed".  In some organisms this difference is so pronounced that their Hb molecules dissociate into dimers in the oxygenated form.  Structural changes that occur during this transition can illuminate how such changes result in important functional properties, such as cooperativity of oxygen binding and allosteric control by pH and anions.
+For hemoglobin to function as an oxygen-carrier in the blood, it must have an equilibrium between the two main states of its quaternary structure, the unliganded "deoxy" or "T state" versus the liganded "oxy" or "R state".  The unliganded (deoxy) form is called the "T" (for "tense") state because it contains extra stabilizing interactions between the subunits, specifically <scene name='57/576710/Deoxy_salt_bridges/3'>ionic interactions</scene>.  In the high oxygen affinity R-state conformation, these ionic interactions <scene name='57/576710/Oxy_ionic_interactions/1'>are lost</scene>, and the tetramer is described as "relaxed".  In some organisms this difference is so pronounced that their Hb molecules dissociate into dimers in the oxygenated form.  Structural changes that occur during this transition can illuminate how such changes result in important functional properties, such as cooperativity of oxygen binding and allosteric control by pH and anions.
-The Bohr effect is the increased stability of the T state due to protonation of histidine residues, especially <scene name='57/576710/Bohr_effect/2'>His 146</scene> of the beta chains.  This is the C terminal residue of the beta chain.  In the T state, the C terminal carboxylate group interacts with the positively charged side chain of lysine 40 of an alpha chain.  When His 146 is protonated, it can also form an ionic interaction with Asp 94.  This second interaction is one of several interactions which stabilizes the T state at lower pH.
+'''The Bohr effect''' is the increased stability of the T state due to protonation of histidine residues, especially <scene name='57/576710/Bohr_effect/2'>His 146</scene> of the beta chains.  This is the C terminal residue of the beta chain.  In the T state, the C terminal carboxylate group interacts with the positively charged side chain of lysine 40 of an alpha chain.  When His 146 is protonated, it can also form an ionic interaction with Asp 94.  This second interaction is one of several interactions which stabilizes the T state at lower pH.
-Bisphosphoglycerate (BPG) is a biproduct of metabolism; its presence is an indication of increased need for oxygen in the tissues.  It binds in the <scene name='57/576710/Bpg_binding/1'>central cavity</scene> of hemoglobin, but only in the deoxy (T) state.  The binding is due to interactions with <scene name='57/576710/Bpg_binding_residues/2'>positively charged residues</scene>.  In the oxy form, this cavity is much narrower, and BPG cannot bind.
+'''Bisphosphoglycerate (BPG)''' is a biproduct of metabolism; its presence is an indication of increased need for oxygen in the tissues.  It binds in the <scene name='57/576710/Bpg_binding/1'>central cavity</scene> of hemoglobin, but only in the deoxy (T) state.  The binding is due to interactions with <scene name='57/576710/Bpg_binding_residues/2'>positively charged residues</scene>.  In the oxy form, this cavity is much narrower, and BPG cannot bind.
+----
+Other Species
 Some fish exhibit a more extreme stabilization at low pH, to the extent that the fully oxygenated species cannot be generated at atmospheric oxygen concentrations. <ref>PMID: 15117955</ref>  This is due to several ionic interactions not found in the human or mammalian hemoglobins.  A novel salt bridge is found between His-69 and Asp-72 of the beta chains in the T state. Furthermore, <scene name='57/576710/Asp_tyr_asn_deoxy_5/2'>Asp99β1 binds to Tyr43α2</scene>  and Asn99α2 in the T state but not the R state. Additional proton binding to the T state occurs through a pair of carboxyl groups, <scene name='57/576710/Asp_asp_deoxy/2'>Asp-96α1 and Asp-101β2</scene>. These groups share a proton in the T state that is lost in the R state as the two αβ dimers rotate, pulling the carboxyl side chains apart, allowing them to both have a negative charge.  Interestingly, no salt bridge is formed by His-146 at C terminus of the beta chain, in contrast to the Bohr effect seen in human hemoglobin and described above.  This may be because the serine at position 93 is changed to a cysteine in Tuna, which seems to prevent this interaction rather than strengthen it.