The ataxia related G1107D mutation of the plasma membrane Ca2+ ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process

doi:10.1016/j.bbadis.2016.09.007

	The ataxia related G1107D mutation of the plasma membrane Ca2+ ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process
	Cali, Tito 1; Frizzarin, Martina 1; Luoni, Laura 2; Zonta, Francesco3 ; Pantano, Sergio 4; Cruz, Carlos 4,5; Bonza, Maria Cristina 2; Bertipaglia, Ilenia 1; Ruzzene, Maria 1; De Michelis, Maria Ida 2; Damiano, Nunzio 1; Marin, Oriano 1; Zanni, Ginevra 6; Zanotti, Giuseppe 1; Brini, Marisa 7; Lopreiato, Raffaele 1; Carafoli, Ernesto 8
	2017-01
发表期刊	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE (IF:4.2[JCR-2023],5.5[5-Year])
ISSN	0925-4439
卷号	1863 期号:1 页码:165-173
发表状态	已发表
DOI	10.1016/j.bbadis.2016.09.007
摘要	The plasma membrane Ca2+ ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca2+), 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 Ca2+), Ca2+-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 Ca2+ in the activated state, and the autoinhibition mechanism in its resting state. (C) 2016 Published by Elsevier B.V.
关键词	Calcium signaling Plasma membrane calcium ATPases X-linked cerebellar ataxia Calmodulin Autoinhibition
收录类别	SCI
语种	英语
资助项目	FOCEM (MERCOSUR Structural Convergence Fund)[COF 03/11]
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Biophysics ; Cell Biology
WOS记录号	WOS:000390625400017
出版者	ELSEVIER SCIENCE BV
WOS关键词	CALCIUM-PUMP ; SACCHAROMYCES-CEREVISIAE ; ARABIDOPSIS-THALIANA ; CEREBELLAR-ATAXIA ; FORCE-FIELD ; CA-2+ PUMP ; N-TERMINUS ; CA2+-ATPASE ; EXPRESSION ; PROTEINS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1583
专题	免疫化学研究所_特聘教授组_功能筛选实验室免疫化学研究所_特聘教授组_Michael Levitt组
通讯作者	Lopreiato, Raffaele; Carafoli, Ernesto
作者单位	1.Univ Padua, Dept Biomed Sci, I-35131 Padua, Italy 2.Univ Milan, Dept Biosci, I-20122 Milan, Italy 3.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China 4.Inst Pasteur Montevideo, Montevideo, Uruguay 5.Fiocruz MS, Oswaldo Cruz Fdn, CpqAM, Aggeu Magalhaes Res Ctr, Rio De Janeiro, Brazil 6.Bambino Gesu Pediat Hosp, IRCCS, Dept Neurosci, Rome, Italy 7.Univ Padua, Dept Biol, I-35100 Padua, Italy 8.VIMM, I-35131 Padua, Italy
推荐引用方式 GB/T 7714	Cali, Tito,Frizzarin, Martina,Luoni, Laura,et al. The ataxia related G1107D mutation of the plasma membrane Ca2+ ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process[J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE,2017,1863(1):165-173.
APA	Cali, Tito.,Frizzarin, Martina.,Luoni, Laura.,Zonta, Francesco.,Pantano, Sergio.,...&Carafoli, Ernesto.(2017).The ataxia related G1107D mutation of the plasma membrane Ca2+ ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process.BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE,1863(1),165-173.
MLA	Cali, Tito,et al."The ataxia related G1107D mutation of the plasma membrane Ca2+ ATPase isoform 3 affects its interplay with calmodulin and the autoinhibition process".BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 1863.1(2017):165-173.