Solute Transport across Membranes:- P-Type Ca²⁺ Pumps Maintain a Low Concentration of Calcium in the Cytosol

The cytosolic concentration of free Ca²⁺ is generally at or below 100 nM, far lower than that in the surrounding medium, whether pond water or blood plasma. The ubiquitous occurrence of inorganic phosphates (Pi and PPi) at millimolar concentrations in the cytosol necessitates a low cytosolic Ca²⁺ concentration, because inorganic phosphate combines with calcium to form relatively in soluble calcium phosphates. Calcium ions are pumped out of the cytosol by a P-type ATPase, the plasma mem brane Ca²⁺   pump. Another P-type Ca²⁺pump in the endoplasmic reticulum moves Ca²⁺into the ER lumen, a compartment separate from the cytosol. In myocytes, Ca²⁺   is normally sequestered in a specialized form of endoplasmic reticulum called the sarcoplasmic reticulum. The sarcoplasmic and endoplasmic reticulum calcium (SERCA) pumps are closely related in structure and mechanism, and both are inhibited by the tumor-promoting agent thapsigargin, which does not affect the plasma membrane Ca²⁺pump. The plasma membrane Ca²⁺   pump and SERCA pumps are integral proteins that cycle between phosphorylated and dephosphorylated conformations in a mechanism similar to that for Na K ATPase (Fig. 11–37). Phosphorylation favors a conformation with a high-affinity Ca²⁺ -binding site exposed on the cytoplasmic side, and dephosphorylation favors one with a low-affinity Ca²⁺ -binding site on the lumenal side. By this mechanism, the energy released by hydrolysis of ATP during one phosphorylation-dephosphorylation cycle drives Ca²⁺   across the membrane against a large electrochemical gradient.

FIGURE 11–37 Postulated mechanism of Na⁺ and K⁺ transport by the Na⁺ K⁺ ATPase.

The Ca²⁺ pump of the sarcoplasmic reticulum, which comprises 80% of the protein in that membrane, consists of a single polypeptide (Mr ~100,000) that spans the membrane ten times and has three cytoplasmic domains formed by loops that connect the trans membrane helices (Fig. 11–38). The two Ca²⁺-binding sites are located near the middle of the membrane bi layer, 40 to 50 Å from the phosphorylated Asp residue characteristic of all P-type ATPases, so the effects of Asp phosphorylation are not direct. They must be mediated by conformational changes that alter the affinity for Ca²⁺ and open a path for Ca²⁺ release on the lumenal side of the membrane. The amino acid sequences of the SERCA pumps and the Na K ATPase share 30% identity and 65% sequence similarity, and their topology relative to the membrane is also the same. Thus, it seems likely that the Na⁺K⁺ ATPase structure is similar to that of the SERCA pumps and that all P-type ATPase transporters share the same basic structure.

FIGURE 11–38 Structure of the Ca²⁺ pump of sarcoplasmic reticulum. (PDB ID 1EUL) Ten transmembrane helices surround the path for Ca²⁺ movement through the membrane. Two of the helices are interrupted near the middle of the bilayer, and their nonhelical regions form the binding sites for two Ca²⁺ ions (green). The carboxylate groups of an Asp residue in one helix and a Glu residue in another are central to the Ca²⁺-binding sites. Three globular domains extend from the cytoplasmic side: the N (nucleotide-binding) domain has the binding site for ATP; the P (phosphorylation) domain contains the Asp351 residue (blue) that undergoes reversible phosphorylation, and the A (actuator) domain somehow mediates the structural changes that alter the Ca²⁺ affinity of the Ca²⁺-binding site and its exposure to cytoplasm or lumen. Note the long distance between the phosphorylation site and the Ca²⁺-binding site. There is strong evidence that during one transport cycle, the N domain tips about 20 to the right, bringing the ATP site close to Asp351, and that during each catalytic cycle the A domain twists by about 90 around the normal (perpendicular) to the membrane. These conformational changes must expose the Ca²⁺-binding site first on one side of the membrane, then on the other, changing the Ca²⁺ affinity of the site from high on the cytoplasmic side to lower on the lumenal side. A complete understanding of the coupling between phosphorylation and Ca²⁺ transport awaits determination of all the conformations involved in the cycle.

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مواضيع ذات صلة

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Solute Transport across Membranes:- ABC Transporters Use ATP to Drive the Active Transport of a Wide Variety of Substrates

Solute Transport across Membranes:-Active Transport Results in Solute Movement against a Concentration or Electrochemical Gradient

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Solute Transport across Membranes:- Transporters Can Be Grouped into Superfamilies Based on Their Structures

Solute Transport across Membranes:- Passive Transport Is Facilitated by Membrane Proteins

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