TY - GEN
T1 - Protein interactions and disease phenotypes in the ABC transporter superfamily
AU - Kelly, Libusha
AU - Karchin, Rachel
AU - Sali, Andrej
PY - 2007
Y1 - 2007
N2 - ABC transporter proteins couple the energy of ATP binding and hydrolysis to substrate transport across a membrane. In humans, clinical studies have implicated mutations in 19 of the 48 known ABC transporters in diseases such as cystic fibrosis and adrenoleukodystrophy. Although divergent in sequence space, the overall topology of these proteins, consisting of two transmembrane domains and two ATP-binding cassettes, is likely to be conserved across diverse organisms. We examine known intra-transporter domain interfaces using crystallographic structures of isolated and complexed domains in ABC transporter proteins and find that the nucleotide binding domain interfaces are better conserved than interfaces at the transmembrane domains. We then apply this analysis to identify known disease-associated point and deletion mutants for which disruption of domain-domain interfaces might indicate the mechanism of disease. Finally, we suggest a possible interaction site based on conservation of sequence and disease-association of point mutants.
AB - ABC transporter proteins couple the energy of ATP binding and hydrolysis to substrate transport across a membrane. In humans, clinical studies have implicated mutations in 19 of the 48 known ABC transporters in diseases such as cystic fibrosis and adrenoleukodystrophy. Although divergent in sequence space, the overall topology of these proteins, consisting of two transmembrane domains and two ATP-binding cassettes, is likely to be conserved across diverse organisms. We examine known intra-transporter domain interfaces using crystallographic structures of isolated and complexed domains in ABC transporter proteins and find that the nucleotide binding domain interfaces are better conserved than interfaces at the transmembrane domains. We then apply this analysis to identify known disease-associated point and deletion mutants for which disruption of domain-domain interfaces might indicate the mechanism of disease. Finally, we suggest a possible interaction site based on conservation of sequence and disease-association of point mutants.
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M3 - Conference contribution
C2 - 17990484
AN - SCOPUS:38449085899
SN - 9812704175
SN - 9789812704177
T3 - Pacific Symposium on Biocomputing 2007, PSB 2007
SP - 51
EP - 63
BT - Pacific Symposium on Biocomputing 2007, PSB 2007
T2 - Pacific Symposium on Biocomputing, PSB 2007
Y2 - 3 January 2007 through 7 January 2007
ER -