The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations

Abstract

Wilson Disease (WD) is a hereditary genetic disorder, which coincides with a dysfunctional copper (Cu) metabolism caused by mutations in ATP7B, a membrane-bound P 1B -type ATPase responsible for Cu export from hepatic cells. The N-terminal part (* 600 residues) of the multi-domain 1400-residue ATP7B constitutes six metal binding domains (MBDs), each of which can bind a copper ion, interact with other ATP7B domains as well as with different proteins. Although the ATP7B's MBDs have been investigated in vitro and in vivo intensively, it remains unclear how these domains modulate overall structure, dynamics, stability and function of ATP7B. The presence of six MBDs is unique to mammalian ATP7B homologs, and many WD causing missense mutations are found in these domains. Here, we have summarized previously reported in vitro biophysical data on the MBDs of ATP7B and WD point mutations located in these domains. Besides the demonstration of where the research field stands today, this review showcasts the need for further biophysical investigation about the roles of MBDs in ATP7B function. Molecular mechanisms of ATP7B are important not only in the development of new WD treatment but also for other aspects of human physiology where Cu transport plays a role.

Copper relay path through the N-terminus of Wilson disease protein, ATP7B

“…Because specific Atox1 interactions appear to be involved in the Cu transport mechanism among the MBDs in ATP7B, 29 our system, in contrast to previous reports, 14,[31][32][33] includes the exchange of the yeast Cu chaperone (Atx1) for the human one, i.e., Atox1, in addition to exchanging yeast CCC2 for human ATP7B. Although the MBDs have the same fold and Cu site, there are differences in biophysical properties among the six domains, such as electrostatic surface potentials, conformational dynamics and Cu-dependent structural changes, and variations in linker lengths between the domains, [34][35][36] that all may contribute to a preferred Cu transport relay among them. Our finding that one of the Cu sites in MBD56 is essential for Cu transport is supported by our 25 and others' earlier work.…”

Short oligopeptides with three cysteine residues as models of sulphur-rich Cu(i)- and Hg(ii)-binding sites in proteins

“…7,8 Cu(I) can also accommodate a linear CuS 2 -type coordination mode, as indicated by structural data on the copper efflux regulator CueR 9 or the metal binding domains of the copper transporter protein ATP7B. 10 Trigonal CuS 3 centres were proposed in the binuclear Cu(I)-thiolate core of the repressor protein CopY 11 and in one of the suggested metal-bridged dimeric forms of the copper chaperone CopZ, 12 whereas the Cu(I)-bridged HAH1 dimer 7 was shown also to include a fourth, weakly bound, thiolate in a pseudotetrahedral environment.…”

Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics

“…Despite 'only' regulatory roles proposed, and the redundancy of domains, it is interesting to note that at least 33 WD causing missense mutations are found in the MBDs (excluding linker regions) (Arioz et al 2017). The MBDs closest to the membrane-spanning part of ATP7B, MBD5 and MBD6, appear to be a hotspot containing 23 of the 33 missense mutations in the MBDs (Arioz et al 2017;Gourdon et al 2012). Only two of the 33 mutations are localized in the Cubinding motifs.…”