The ataxia related G1107D mutation of the plasma membrane Ca(2+) ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process
| Autor: | Maria Ruzzene, Raffaele Lopreiato, Nunzio Damiano, Martina Frizzarin, Ginevra Zanni, Ernesto Carafoli, Sergio Pantano, Maria Cristina Bonza, Laura Luoni, Marisa Brini, Francesco Zonta, Ilenia Bertipaglia, Oriano Marin, Carlos Cruz, Maria Ida De Michelis, Giuseppe Zanotti, Tito Calì |
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| Přispěvatelé: | Universita degli Studi di Padova, Università degli Studi di Milano [Milano] (UNIMI), Shanghai Institute of Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China., Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP), Fundação Oswaldo Cruz (FIOCRUZ), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Venetian Institute Molecular Medicine (VIMM) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Gene isoform Mutation Calmodulin ATPase [SDV]Life Sciences [q-bio] Wild type Calcium signaling X-linked cerebellar ataxia Biology medicine.disease_cause Autoinhibition 03 medical and health sciences Cytosol 030104 developmental biology Biochemistry medicine biology.protein Biophysics Molecular Medicine Plasma membrane Ca2+ ATPase Plasma membrane calcium ATPases Molecular Biology |
| Zdroj: | BBA-Biochimica et Biophysica Acta BBA-Biochimica et Biophysica Acta, Elsevier, 2017, 1863 (1), pp.165-173. ⟨10.1016/j.bbadis.2016.09.007⟩ |
| ISSN: | 0006-3002 |
| Popis: | International audience; The plasma membrane Ca(2+) ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca(2+)), the C-terminal tail of the pump interacts with autoinhibitory sites proximal to the active center of the enzyme. In activating conditions (i.e., high Ca(2+)), Ca(2+)-bound CaM displaces the C-terminal tail from the autoinhibitory sites, restoring activity. We have recently identified a G1107D replacement within the CaM-BD of isoform 3 of the PMCA pump in a family affected by X-linked congenital cerebellar ataxia. Here, we investigate the effects of the G1107D replacement on the interplay of the mutated CaM-BD with both CaM and the pump core, by combining computational, biochemical and functional approaches. We provide evidence that the affinity of the isolated mutated CaM-BD for CaM is significantly reduced with respect to the wild type (wt) counterpart, and that the ability of CaM to activate the pump in vitro is thus decreased. Multiscale simulations support the conclusions on the detrimental effect of the mutation, indicating reduced stability of the CaM binding. We further show that the G1107D replacement impairs the autoinhibition mechanism of the PMCA3 pump as well, as the introduction of a negative charge perturbs the contacts between the CaM-BD and the pump core. Thus, the mutation affects both the ability of the pump to optimally transport Ca(2+) in the activated state, and the autoinhibition mechanism in its resting state. |
| Databáze: | OpenAIRE |
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