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

ABC transporters (Fig. 11–41) constitute a large family of ATP-dependent transporters that pump amino acids, peptides, proteins, metal ions, various lipids, bile salts, and many hydrophobic compounds, including drugs, out of cells against a concentration gradient. One ABC transporter in humans, the multi drug transporter (MDR1), is responsible for the striking resistance of certain tumors to some generally effective antitumor drugs. MDR1 has a broad substrate specificity for hydrophobic compounds, including, for example, the chemotherapeutic drugs adriamycin, doxorubicin, and vinblastine. By pumping these drugs out of the cell, the transporter prevents their accumulation within a tumor and thus blocks their therapeutic effects. MDR1 is an integral membrane protein (Mr 170,000) with 12 transmembrane segments and two ATP-binding domains (“cassettes”), which give the family its name: ATP-binding cassette transporters.

All ABC transporters have two nucleotide-binding domains (NBDs) and two transmembrane domains (Fig. 11–41). In some cases, all these domains are in a single long polypeptide; other ABC transporters have two sub units, each contributing an NBD and a domain with six (or in some cases ten) transmembrane helices. Although many of the ABC transporters are in the plasma mem brane, some types are also found in the endoplasmic reticulum and in the membranes of mitochondria and lysosomes. Most ABC transporters act as pumps, but at least some members of the superfamily act as ion channels that are opened and closed by ATP hydrolysis. The CFTR transporter (Box 11–3) is a Cl channel operated by ATP hydrolysis.

The NBDs of all ABC proteins are similar in sequence and presumably in three-dimensional structure; they are the conserved molecular motor that can be coupled to a wide variety of pumps and channels. When coupled with a pump, the ATP-driven motor moves solutes against a concentration gradient; when coupled with an ion channel, the motor opens and closes the channel using ATP as energy source. The stoichiometry of ABC pumps is about one ATP hydrolyzed per molecule of substrate transported, but neither the mechanism of coupling nor the site of substrate binding are known.

Some ABC transporters have very high speci ficity for a single substrate; others are more promiscuous. The human genome contains at least 48 genes that encode ABC transporters, many of which are involved in maintaining the lipid bilayer and in trans porting sterols, sterol derivatives, and fatty acids throughout the body. The flippases that move mem brane lipids from one leaflet of the bilayer to the other are ABC transporters, and the cellular machinery for ex porting excess cholesterol includes an ABC transporter. Mutations in the genes that encode some of these proteins contribute to several genetic diseases, including cystic fibrosis, Tangier disease, retinal degeneration, anemia, and liver failure. ABC transporters are also present in simpler animals and in plants and microorganisms. Yeast has 31 genes that encode ABC transporters, Drosophila has 56, and E. coli has 80, representing 2% of its entire genome. The presence of ABC transporters that confer antibiotic resistance in pathogenic microbes (Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, Neisseria gonorrhoeae, and Plasmodium falciparum) is a serious public health concern and makes these transporters attractive targets for drug design.

FIGURE 11–41 Structures of two ABC trans porters of E. coli. (a) The lipid A flippase MsbA (PDB ID 1JSQ) and (b) the vitamin B12 importer BtuCD (PDB ID 1L7V). Both structures are homodimers. The two nucleotide binding domains (NBDs, in red) extend into the cytoplasm. In (b), residues involved in ATP binding and hydrolysis are shown as ball and-stick structures. Each monomer of MsbA has six transmembrane helical segments (blue), and each monomer of BtuCD has ten.

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قسم الشؤون الفكرية يضمّ جامعتي العميد والكفيل إلى مشروعي الملف الاستنادي والبوابة العراقية

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تكريم إدارات المدارس المشاركة في مسابقة بصائر العلم الوطنية الأولى

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خبير يكشف 5 حقائق طبية صادمة وغير معروفة

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دراسة حديثة تفند ربط التستوستيرون بالمخاطرة لدى الرجال

ميتا تضيف وضع "المحادثة المخفية" إلى تطبيق "واتساب"

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مواضيع ذات صلة

Solute Transport across Membranes:- Ion-Selective Channels Allow Rapid Movement of Ions across Membranes

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

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

Solute Transport across Membranes:-The Chloride-Bicarbonate Exchanger Catalyzes Electroneutral Cotransport of Anions across the Plasma Membrane

Solute Transport across Membranes:- The Glucose Transporter of Erythrocytes Mediates Passive Transport

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

Membrane Dynamics:- Membrane Fusion Is Central to Many Biological Processes

The Composition and Architecture of Membranes:- Sphingolipids and Cholesterol Cluster Together in Membrane Rafts

The Composition and Architecture of Membranes:- Peripheral Membrane Proteins Are Easily Solubilized

The Composition and Architecture of Membranes:- A Lipid Bilayer Is the Basic Structural Element of Membranes

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Cooperative Ligand Binding Can Be Described