#ATP-binding cassette

Membrane Transportation

Which of the following describes the Walker A sequence in ABC transporters?

Walker A motif, discovered by John Walker through alignment of ATP synthase beta subunit, kinases and ABC proteins, is phosphate-binding P-loop with consensus GXXGXGKT/S where X denotes any residue. In ABC nucleotide-binding domains this loop lies at N-terminus of alpha-helix following central beta-sheet, with invariant lysine side chain forming ion pair with beta and gamma phosphates of ATP and conserved threonine or serine coordinating Mg2+ ion essential for hydrolysis. Together with Walker B aspartate that chelates Mg2+ and signature LSGGQ from opposite NBD completing active site, Walker A

Ref: Walker et al., EMBO J 1982, P-loop motifs; Jones & George, Cell Mol Life Sci 2004, NBD mechanism.

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Membrane Transportation

Which of the following is a feature of ABC ATPase pumps?

A unifying structural signature distinguishes ABC ATPase pumps from other transporter classes like P-type or SLC carriers. Functionally active unit requires two hydrophobic transmembrane domains, each generally composed of six alpha-helices that create substrate-binding chamber accessible alternately to cytoplasm or extracellular milieu, and two peripherally located nucleotide-binding domains in cytoplasm that dimerize upon ATP ligation. The nucleotide-binding domains contain highly conserved Walker A, Walker B, Q-loop, D-loop, H-loop and ABC signature LSGGQ motif that contacts ATP across dime

Ref: Locher, Nature 2016, Mechanistic diversity ABC transporters; Alberts, 7th ed., Chapter 11 structure.

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Membrane Transportation

What is the function of ABC transporters?

ATP-binding cassette superfamily includes hundreds of members across all domains of life encoded by 49 human genes divided into ABCA to ABCG subfamilies. Core architecture comprises two transmembrane domains forming substrate path and specificity filter, and two cytosolic nucleotide-binding domains containing Walker A P-loop GXXGXGKS/T for phosphate binding, Walker B hhhhDE coordinating Mg2+ and catalytic glutamate, and signature LSGGQ hallmark. ATP binding drives NBD dimerization sandwiching two ATPs, converting TMDs to outward-facing conformation; hydrolysis and release of ADP and Pi resets

Ref: Dean et al., Genome Res 2001, Human ABC family; Rees et al., Nat Rev Mol Cell Biol 2009.

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Membrane Transportation

What is the function of the ABC transporter superfamily?

ATP-binding cassette superfamily constitutes one of largest and most functionally diverse transporter groups present in all domains of life, with 48 members in human genome implicated in cystic fibrosis, Tangier disease and multidrug resistance. Each functional unit minimal consists of two transmembrane domains typically six helices each forming translocation pathway determining substrate specificity and two cytosolic nucleotide binding domains containing highly conserved Walker A P-loop GXXGXGKS binding phosphate, Walker B hhhhDE binding magnesium, signature motif LSGGQ unique to ABC, and Q-l

Ref: Dean et al., Genome Research, ABC Transporter Superfamily Substrates and Multidrug Resistance.

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