Sazinsky Matthew H, Agarwal Sorabh, Argüello José M, Rosenzweig Amy C
Department of Biochemistry, Northwestern University, Evanston, Illinois 60208, USA.
Biochemistry. 2006 Aug 22;45(33):9949-55. doi: 10.1021/bi0610045.
Copper homeostasis is maintained in part by membrane-bound P(1B)-type ATPases that are found in all organisms and drive the transport of this essential, yet toxic, metal ion across cellular membranes. CopA from Archaeoglobus fulgidus is a hyperthermophilic member of this ATPase subfamily and is homologous to the human Wilson and Menkes disease ATPases. To gain insight into Cu(+)-ATPase function, the structure of the CopA actuator domain (A-domain) was determined to 1.65 A resolution. The CopA A-domain functions to couple ATP hydrolysis in the ATP binding domain (ATPBD) with structural rearrangements of critical transmembrane segments. Its fold is quite similar to that of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA1) A-domain, with the exception of an external loop region. On the basis of sequence and structural comparisons, specific residues that probably interact with the CopA ATPBD have been identified. Comparisons to the Wilson and Menkes disease A-domains reveal the presence of an additional loop that may be associated with regulatory functions in eukaryotic Cu(+)-ATPases. Finally, several mutations in the Wilson and Menkes disease ATPases occur in the A-domain, and their likely effects on function can be inferred from the CopA A-domain structure.
铜稳态部分由膜结合的P(1B)型ATP酶维持，这些酶存在于所有生物体中，驱动这种必需但有毒的金属离子跨细胞膜运输。来自嗜热栖热菌的CopA是该ATP酶亚家族的嗜热成员，与人类威尔逊病和门克斯病ATP酶同源。为了深入了解铜离子ATP酶的功能，CopA驱动域（A域）的结构被解析到1.65 Å的分辨率。CopA A域的功能是将ATP结合域（ATPBD）中的ATP水解与关键跨膜片段的结构重排相偶联。其折叠结构与肌浆网钙ATP酶（SERCA1）A域非常相似，除了一个外部环区域。基于序列和结构比较，已鉴定出可能与CopA ATPBD相互作用的特定残基。与威尔逊病和门克斯病A域的比较揭示了一个额外环的存在，该环可能与真核铜离子ATP酶的调节功能有关。最后，威尔逊病和门克斯病ATP酶中的几个突变发生在A域，其对功能的可能影响可从CopA A域结构推断出来。
