ABCMdb

PMID: 11804194

Sun H, Nathans J
Mechanistic studies of ABCR, the ABC transporter in photoreceptor outer segments responsible for autosomal recessive Stargardt disease.
J Bioenerg Biomembr. 2001 Dec;33(6):523-30., [PubMed]

Sentences

No. Mutations Sentence Comment

94 ABCA4 p.Leu541Pro ABCA4 p.Trp1408Arg Among these are L541P, predicted to reside adjacent to a transmembrane domain, and W1408R, which resides between the homologous halves of ABCR. These data suggest that ATP binding to the two NBDs is allosterically coupled to conformational changes in or near the transmembrane regions. Login to comment 96 ABCA4 p.Gly1961Glu ABCA4 p.Thr971Asn Figure 4(A) and (B) illustrates the behavior of two of these variants, T971N and G1961E, which reside within NBD-1 and NBD-2, respectively. Login to comment 97 ABCA4 p.Thr971Asn T971N shows little basal ATPase and little or no retinal-stimulated ATPase; it is also defective in azido-ATP labeling. Login to comment 98 ABCA4 p.Gly1961Glu G1961E exhibits reduced basal ATPase activity, and the ATPase activity shows inhibition by retinal rather than stimulation. Login to comment 99 ABCA4 p.Ala1038Val ABCA4 p.Thr971Asn Among the variants tested in NBD-1, T971N and A1038V have a lower 528 Sun and Nathans Fig. 4. Login to comment 104 ABCA4 p.Thr971Asn (A) Naturally occurring variant T971N in NBD-1. Login to comment 105 ABCA4 p.Gly1961Glu (B) Naturally occurring variant G1961E in NBD-2. Login to comment 106 ABCA4 p.Gly1975Asp ABCA4 p.Gly1975Asp ABCA4 p.Gly966Asp ABCA4 p.Gly966Asp (C) Synthetic substitutions of a conserved glycine in the Walker A motif of NBD-1 (G966D), NBD-2 (G1975D), or both (G966D/G1975D). Login to comment 107 ABCA4 p.Lys1978Met ABCA4 p.Lys1978Met ABCA4 p.Lys969Met ABCA4 p.Lys969Met (D) Synthetic substitutions of a conserved lysine in the Walker A motif of NBD-1 (K969M), NBD-2 (K1978M), or both (K969M/K1978M). Login to comment 108 ABCA4 p.Asn965Ser basal ATPase activity than N965S, and all three show little or no retinal-stimulated ATP hydrolysis. Login to comment 109 ABCA4 p.Gly1961Glu ABCA4 p.Gly1977Ser ABCA4 p.Leu1971Arg ABCA4 p.Glu2096Lys Among the variants tested in NBD-2, L1971R eliminates both basal and retinal-stimulated ATP hydrolysis, whereas G1977S and E2096K resemble G1961E in showing inhibition rather than stimulation of ATPase by retinal. Login to comment 110 ABCA4 p.Ala1038Val ABCA4 p.Leu1971Arg ABCA4 p.Thr971Asn The complete or nearly complete elimination of all ATPase activity produced by single NBD mutations-T971N, A1038V, or L1971R-implies that the two NBDs are allosterically coupled. Login to comment 114 ABCA4 p.Gly1961Glu ABCA4 p.Gly1977Ser ABCA4 p.Lys1978Met ABCA4 p.Lys1978Met ABCA4 p.Lys969Met ABCA4 p.Lys969Met ABCA4 p.Glu2096Lys ABCA4 p.Gly1975Asp ABCA4 p.Gly1975Asp ABCA4 p.Gly966Asp ABCA4 p.Gly966Asp When purified, reconstituted, and tested for ATPase activity, the synthetic mutations show (1) that mutations in NBD-1 (G966D or K969M), either alone or in combination with mutations in NBD-2 (G966D/G1975D or K969M/K1978M), abolish both basal and retinal-stimulated ATP hydrolysis and (2) that mutations in NBD-2 (G1975D or K1978M) do not alter the basal ATPase activity but lead to inhibition rather than stimulation of ATP hydrolysis by retinal (Fig. 4(C) and (D)), a pattern noted above for the naturally occurring NBD-2 mutations G1961E, G1977S, and E2096K. Login to comment