ATP7A and ATP7B are two human P1B-type ATPases that have a crucial role in maintaining copper(I) homeostasis. Among the various domains of these enzymes, one, called the Actuator or A-domain, has a regulatory function and is required for the phosphatase step of the catalytic cycle (dephosphorylation of the intermediate formed during ATP hydrolysis). Here we report the solution structures of the A-domain of both proteins, solved by heteronuclear NMR spectroscopy and a characterization of the dynamics of the A-domain of ATP7A. We observed that the catalytically important TGE loop protrudes from the structure ready for interaction with the phosphorilated site in the ATP-binding domain. The loop is rigid, suggesting that the catalytic step does not require substantial structural flexibility or rearrangements. The present structures were useful to rationalize the molecular effects of disease-causing mutations. In particular, it can be concluded that mutations occurring in the A-domain either destabilize the fold of the domain (such as Gly860Val in ATP7A) or affect the network of communication within the domain (such as Leu873Arg in ATP7A) or with the other domains of the enzyme (such as Gly853Arg in ATP7A). © 2009 American Chemical Society.

Solutions structures of the actuator domain of ATP7A and ATP7B, the menkes and wilson disease proteins / L.Banci; I.Bertini; F.Cantini; M.Migliardi; G.Natile; F.Nushi; A.Rosato. - In: BIOCHEMISTRY. - ISSN 0006-2960. - STAMPA. - 48:(2009), pp. 7849-7855. [10.1021/bi901003k]

Solutions structures of the actuator domain of ATP7A and ATP7B, the menkes and wilson disease proteins

BANCI, LUCIA;BERTINI, IVANO;CANTINI, FRANCESCA;MIGLIARDI, MANUELE;ROSATO, ANTONIO
2009

Abstract

ATP7A and ATP7B are two human P1B-type ATPases that have a crucial role in maintaining copper(I) homeostasis. Among the various domains of these enzymes, one, called the Actuator or A-domain, has a regulatory function and is required for the phosphatase step of the catalytic cycle (dephosphorylation of the intermediate formed during ATP hydrolysis). Here we report the solution structures of the A-domain of both proteins, solved by heteronuclear NMR spectroscopy and a characterization of the dynamics of the A-domain of ATP7A. We observed that the catalytically important TGE loop protrudes from the structure ready for interaction with the phosphorilated site in the ATP-binding domain. The loop is rigid, suggesting that the catalytic step does not require substantial structural flexibility or rearrangements. The present structures were useful to rationalize the molecular effects of disease-causing mutations. In particular, it can be concluded that mutations occurring in the A-domain either destabilize the fold of the domain (such as Gly860Val in ATP7A) or affect the network of communication within the domain (such as Leu873Arg in ATP7A) or with the other domains of the enzyme (such as Gly853Arg in ATP7A). © 2009 American Chemical Society.
2009
48
7849
7855
L.Banci; I.Bertini; F.Cantini; M.Migliardi; G.Natile; F.Nushi; A.Rosato
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/368681
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 35
  • ???jsp.display-item.citation.isi??? 29
social impact