ABC transporter

ABC转运蛋白简介

ABC transporter1 What is the ABC transporter? 2 Function 3 Structure 4 Mechanism of transport 5 ABC importers 6 ABC exporters 7 Role in multidrug resistance 8 Reversal of multidrug resistance 9 Physiological role 10 Methods to characterize ABC transporter

ABC转运蛋白简介

1 What is the ABC transporter? Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding cassette (ABC) domain(s) . ATP-binding cassette transporters ( ABC-transporter ) are transmembrane proteins that utilize the energy of adenosine triphosphate (ATP) hydrolysis to carry out certain biological processes including translocation of various substrates across membranes and non-transport-related processes such as translation of RNA and DNA repair. ABC transporters are involved in tumour resistance, cystic fibrosis, bacterial multidrug resistance, and a range of other inherited human diseases.

ABC转运蛋白简介

2 Function2.1 Prokaryotic ABC proteins 2.2 Eukaryotic ABC proteins

ABC转运蛋白简介

ABC transporters utilize the energy of ATP hydrolysis to transport various substrates across cellular membranes. They are divided into three main functional categories. Importers(in prokaryotes) Exporters or effluxers(in both prokaryotes and eukaryotes) The third subgroup do not function as transporters,but are rather involved in translation of RNA and DNA repair processes.

ABC转运蛋白简介

2.1 Prokaryotic ABC proteins Bacterial ABC importers are essential in cell viability, virulence and pathogenicity. Other than functioning in transport, some bacterial ABC proteins are also involved in the regulation of several physiological processes. In bacterial efflux systems, certain substances include surface components of the bacterial cell, proteins involved in bacterial pathogenesis and so on. They also play important roles in biosynthetic pathways.

ABC转运蛋白简介

2.2 Eukaryotic ABC proteins Although most eukaryotic ABC transporters are effluxers, some are not directly involved in transporting substrates. Human ABC transporters are involved in several diseases that arise from polymorphisms in ABC genes and rarely due to complete loss of function of single ABC proteins. More recently, ABC-transporters have been shown to exist within the placenta.

ABC转运蛋白简介

3 Structure3.1 Transmembrane domain (TMD) 3.2 Nucleotide-binding domain (NBD) 3.3 ATP binding and hydrolysis

ABC转运蛋白简介

TMD(transmembrane domain), also known as membrane-spanning domain (MSD) or integral membrane (IM) domain, consists of alpha helices, embedded in the membrane bilayer. NBD(nucleotide-binding domain) or ATPbinding cassette (ABC) domain, on the other hand, is located in the cytoplasm and has a highly conserved sequence.

ABC转运蛋白简介

The structural architecture of ABC transporters consists minimally of two TMDs and two ABCs. Four individual polypeptide chains including two TMD and two NBD subunits, may combine to form a full transporter. Most exporters are made up of a homodimer consisting of two half transporters or monomers of a T

MD fused to a nucleotide-binding domain (NBD). Some ABC transporters have additional elements.

ABC转运蛋白简介

3.1 Transmembrane domain (TMD)three distinct sets of folds: type I ABC importer type II ABC importer ABC exporter folds

ABC转运蛋白简介

3.2 Nucleotide-bind ing domain (NBD)the catalytic core subdomainNBD α-helical subdomain

ABC转运蛋白简介

ABC转运蛋白简介

The catalytic core domain consists of two βsheets and six α helices, where the catalytic Walker A motif (GXXGXGKS/T where X is any amino acid) or P-loop and Walker B motif (ΦΦΦΦD, of which Φ is a hydrophobic residue) is situated. The helical domain consists of three or four helices and the ABC signature motif, also known as LSGGQ motif, linker peptide or C motif.

ABC转运蛋白简介

The ABC domain also has a glutamine residue residing in a flexible loop called Q loop , lid or γ-phosphate switch, that connects the TMD and ABC. The H motif or switch region contains a highly conserved histidine residue that is also important in the interaction of the ABC domain with ATP.

ABC转运蛋白简介

3.3 ATP binding and hydrolysis Dimer formation of the two ABC domains of transporters requires ATP binding. Two molecules of ATP are positioned at the interface of the dimer, sandwiched between the Walker A motif of one subunit and the LSGGQ motif of the other. 目前有两种观点：一种观点认为两个ATP先后 水解，然后二聚体解离；另外一个观点认为一 个ATP先水解，其结合位点打开，当它再结合 ATP时，第二个ATP才开始水解，此为两个ATP 交互水解模式。

ABC转运蛋白简介

4 Mechanism of transport alternating-access model ATP-switch model transport cycle of ABC transporters the driving force of transporter function

ABC转运蛋白简介

alternating-access model In this model, the substrate binding site alternates between outward- and inwardfacing conformations. The relative binding affinities of the two conformations for the substrate largely determines the net direction of transport.

ABC转运蛋白简介

ATP-switch modelThis model presents two principal conformations of the NBDs: formation of a closed dimer upon binding two ATP molecules and dissociation to an open dimer facilitated by ATP hydrolysis and release of inorganic phosphate (Pi) and adenosine diphosphate (ADP).

ABC转运蛋白简介

transport cycle of ABC transportersan open dimer configuration binding of substrate to the TMDs conformational changes in the NBDs the binding of ATP the closed dimer configuration conformational change in the TMDs release of the substrate

ABC转运蛋白简介

the driving force of transporter functionATP binding rather than ATP hydrolysis

ABC转运蛋白简介

5 ABC importers5.1 Common features 5.2 Large ABC importers 5.3 Small ABC importers 5.4 Mechanism of transport for importers

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