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with an extracellularly located amino terminus for ABCC1.
67
−
69
Computational anal-
ysis of rat Abcc2 also predicted an extracellular localization of the amino terminus.
41
Further, an antibody against the amino-terminal sequence of human ABCC2 con-
firmed the extracellular localization of the amino terminus by immunofluorescence
microscopy.
70
On the basis of sequence similarity, it is expected that ABCC3, ABCC6,
ABCC8 (SUR1), ABCC9 (SUR2), and ABCC10 share this topological feature with
an additional extracellular amino-terminal MSD0.
47
,
48
,
58
,
59
,
71
In contrast, a topology
model with two MSDs and an intracellular amino terminus is predicted for ABCC4,
ABCC5, ABCC7, ABCC11, and ABCC12 in a manner similar to that for MDR1
P-glycoprotein.
25
,
72
,
73
Several
N
-glycosylation sites have been identified in the ABCC protein sequences,
especially for ABCC1 and ABCC2
67
; however, site-directed mutagenesis of these
specific amino acids did not alter sorting, transport properties, and substrate specificity
of ABCC1.
67
,
74
11.3.2. Amino Acid Sequence Identities of Human ABCC/MRP Paralogs
The deduced amino acid sequence lengths of the nine human ABCCs/MRPs range
between 1325 amino acids for ABCC4 and 1545 amino acids for ABCC2 (Table 11.1).
Within the complete human ABCC subfamily, the sulfonylurea receptors ABCC8
(SUR1) and ABCC9 (SUR2A and SUR2B) comprise 1581 and 1549 amino acids,
respectively, thus being the longest proteins of the ABCC subfamily. In comparison
with ABCC1, ABCC3 shares 58% amino acid identity and is the member closest
to ABCC1 (Table 11.1). In contrast, CFTR (ABCC7) shares only 30% amino acid
identity with ABCC1 and thus has the lowest amino acid sequence identity. The
ABCC/MRP members that have the same topology as ABCC1 are also those most
closely related to ABCC1 (Table 11.1).
11.3.3. ABCC/MRP Orthologs in Other Species and Phylogenetic Analysis
A number of Abcc/Mrp orthologs has been identified in several mammalian species
and to a minor extent in other vertebrates. At present, seven rat orthologs (Abcc1
to Abcc6 and Abcc12) and eight mouse orthologs (Abcc1-6, Abcc10, and Abcc12)
have been described (Figure 11.1
b
). In addition to humans, rat and mouse are thus
the mammalian species with the largest number of known full-length Abcc/Mrp
sequences. Phylogenetic analysis of the multiple amino acid sequence alignments
shows the high degree of homology among human, rat, and mouse ABCC/MRP or-
thologs (Figure 11.1
b
). For ABCC1, the full-length sequences from five mammalian
species are currently known, including those from human, rat, mouse, dog, and cow,
with amino acid sequence identities ranging between 87 and 91%. ABCC2/Abcc2
full-length sequences have been identified in human, rat, mouse, rabbit, dog, and
rhesus monkey, in addition to chicken, zebrafish, and little skate, with amino acid
sequence identities varying between 57% for the little skate Abcc2 and 96% for the
rhesus monkey Abcc2 compared to the human ABCC2. In addition, the ABCC4
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