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ATP Driven Pumps II: P-type Pumps

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The P-type pumps or P-type ATPases are a type of ATP-driven membrane transporters.

One of the most common examples of P-type pumps are the sarco/endoplasmic reticulum Ca-ATPase or SERCA present on the sarcoplasmic reticulum or SR membrane in the skeletal muscles.

The pump has a transmembrane domain and a cytoplasmic headpiece consisting of three domains: N, nucleotide-binding, P, phosphorylation, and A, actuator.

ATP is bound to the N-domain of the pump. Then, two calcium ions from the cytosolic side bind to the calcium-binding site present within the membrane-spanning domain.

The ATP is then hydrolyzed to ADP and inorganic phosphate. The inorganic phosphate attaches to the P-domain.

The ADP dissociates, followed by binding a new ATP molecule triggering a conformational change in the pump that opens the passageway to the SR lumen and releases the calcium ions. Two hydrogen ions from the SR lumen bind to the empty calcium-binding sites closing the passageway to the lumen.

After this, the inorganic phosphate from the P-domain dissociates. The hydrogen ions temporarily bound to the calcium-binding sites are released, and the pump returns to its initial conformation.

Overview

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The P-type pumps are a large family of integral membrane transporter ATPases. They are divided into five major types based on substrate specificity, from I to V.

A typical P-type pump has three cytosolic domains: nucleotide-binding (N), phosphorylation (P), and activator (A) domains. These domains are connected to the membrane-spanning helices by short amino acid segments. ATP hydrolysis and covalent phosphoenzyme intermediate formation are crucial parts of the catalytic cycle. At the highly conserved cytoplasmic P-domain, the aspartic acid residue is reversibly phosphorylated, which leads to conformational changes in the pumps' transmembrane segments. The A domain allows the association of N and P-domains necessary for the pump's proper functioning, allowing the solute to be translocated across the membrane. This type of structure assembly is seen in Na⁺/K⁺-ATPase, gastric H⁺-ATPase, and Ca²⁺-ATPase pumps.

One of the most important types is Type II, exemplified by the calcium pump, which is essential for maintaining the cellular homeostasis of calcium ions (Ca²⁺). The sodium-calcium exchanger and calcium pumps on the mitochondria and the endoplasmic reticulum (ER) regulate intracellular calcium concentration in the cells. Calcium pumps account for about 80% of the sarcoplasmic reticulum (SR) membrane protein in skeletal muscles. Two calcium ions are transported into the sarcoplasmic reticulum against their concentration gradient for one ATP molecule hydrolyzed. They play a crucial role in cell signaling by ensuring that the cytoplasmic calcium concentration is roughly 10,000 times lesser than the extracellular concentration. Failure to maintain this concentration is one of the causes of muscle cramps.

The calcium pumps in the endo(Sarco)plasmic reticulum are termed the Sarco/Endoplasmic Reticulum Ca²⁺-ATPase (SERCA) pumps, primarily found on the skeletal and heart muscles. When present on the cell's plasma membrane, they are called Plasma Membrane Ca²⁺-ATPase (PMCA) pumps. PMCA pumps are expressed in various tissues, including the brain. The Golgi membrane calcium pumps are termed Secretory Pathway Ca²⁺-ATPase (SPCA) pumps. All these pumps are P-type ATPase pumps.

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