Family 3.A.1 - The ATP-Binding Cassette Family
Family ID: 52649
The ABC superfamily contains both uptake and efflux transport
systems, and the members of these two porter groups generally
cluster loosely together with just a few exceptions. ATP hydrolysis
without protein phosphorylation energizes transport. There are
dozens of families within the ABC superfamily, and family generally
correlates with substrate specificity. However there are exceptions.
The porters
of the ABC superfamily consist of two integral membrane domains/proteins
and two cytoplasmic domains/proteins. The uptake systems (but
not the efflux systems) additionally possess extracytoplasmic
solute-binding receptors (one or more per system) which in Gram-negative
bacteria is found in the periplasm, and in Gram-positive bacteria
is present either as a lipoprotein, tethered to the external surface
of the cytoplasmic membrane, or as a cell surface-associated protein,
bound to the external membrane surface via electrostatic interactions.
Both the integral membrane channel constituent(s) and the cytoplasmic
ATP-hydrolyzing constituent(s) may be present as homodimers or
heterodimers. The homodimeric LmrA drug efflux pump (TC #3.A.1.117.1)
of Lactococcus lactisappears to function by an alternating site
(half of sites) type mechanism. In many of these porters, the
various domains are fused in a variety of combinations. Uptake
porters generally have their constituents as distinct polypeptide
chains, while efflux systems usually have them fused. ABC-type
uptake systems have not been identified in eukaryotes, but ABC-type
efflux systems abound in both prokaryotes and eukaryotes. The
eukaryotic efflux systems often have the four domains (two cytoplasmic
domains and two integral membrane domains) fused into either one
or two polypeptide chains. The integral membrane porter domains
each usually possesses 5 (uptake) or 6 (efflux) transmembrane
spanners, but exceptions exist. For example, the MntB protein
(TC #3.A.1.15.1) exhibits 9 established TMSs. The 3-dimensional
structure of the E. coliMsbA protein (TC #3.A.1.106.1) has been
solved to a resolution of 4.5Å (Chang and Roth, 2001).
The three
structurally dissimilar constituents of the ABC uptake porters
have generally arisen from a common ancestral porter system with
minimal shuffling of constituents between systems. Thus, phylogenetic
clustering of the three protein/domain constituents is almost
always the same. However the rates of sequence divergences differ
drastically with the extracytoplasmic solute-binding receptors
diverging most rapidly, the integral-membrane, channel-forming
constituents diverging at an intermediate rate, and the cytoplasmic
ATP-hydrolyzing constituents diverging most slowly. Thus, all
ATP-hydrolyzing constituents are demonstrably homologous, but
this is not true for the integral membrane constituents or the
receptors. Nevertheless, clustering patterns are generally the
same for all three types of proteins, and 3-dimensional structural
data suggest that, in spite of their extensive sequence
