Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity

被引:59
作者
Chernorudskiy, Alexander [1 ]
Varone, Ersilia [1 ]
Colombo, Sara Francesca [2 ,3 ]
Fumagalli, Stefano [1 ]
Cagnotto, Alfredo [1 ]
Cattaneo, Angela [4 ]
Briens, Mickael [5 ]
Baltzinger, Mireille [5 ]
Kuhn, Lauriane [5 ]
Bachi, Angela [6 ]
Berardi, Andrea [7 ]
Salmona, Mario [1 ]
Musco, Giovanna [7 ]
Borgese, Nica [2 ,3 ]
Lescure, Alain [5 ]
Zito, Ester [1 ]
机构
[1] Ist Ric Farmacol Mario Negri IRCCS, I-20156 Milan, Italy
[2] CNR, Inst Neurosci, I-20129 Milan, Italy
[3] Univ Milan, BIOMETRA Dept, I-20129 Milan, Italy
[4] Cogentech SRL Benefit Corp, Prote MS Facil, I-20139 Milan, Italy
[5] Univ Strasbourg, CNRS, Architecture & Reactivite ARN, F-67084 Strasbourg, France
[6] IFOM FIRC Inst Mol Oncol, I-20139 Milan, Italy
[7] IRCCS Osped S Raffaele, Biomol NMR Unit, I-20132 Milan, Italy
关键词
calcium sensor; SEPN1; endoplasmic reticulum; stress of the endoplasmic reticulum; SECONDARY STRUCTURE; CA2+ SENSOR; HOMEOSTASIS; CHANNEL; DYSFUNCTION; PROTEINS; STORE; STIM1; SEPN1;
D O I
10.1073/pnas.2003847117
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The endoplasmic reticulum (ER) is the reservoir for calcium in cells. Luminal calcium levels are determined by calcium-sensing proteins that trigger calcium dynamics in response to calcium fluctuations. Here we report that Selenoprotein N (SEPN1) is a type II transmembrane protein that senses ER calcium fluctuations by binding this ion through a luminal EF-hand domain. In vitro and in vivo experiments show that via this domain, SEPN1 responds to diminished luminal calcium levels, dynamically changing its oligomeric state and enhancing its redox-dependent interaction with cellular partners, including the ER calcium pump sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Importantly, single amino acid substitutions in the EF-hand domain of SEPN1 identified as clinical variations are shown to impair its calcium-binding and calcium-dependent structural changes, suggesting a key role of the EF-hand domain in SEPN1 function. In conclusion, SEPN1 is a ER calcium sensor that responds to luminal calcium depletion, changing its oligomeric state and acting as a reductase to refill ER calcium stores.
引用
收藏
页码:21288 / 21298
页数:11
相关论文
共 33 条
[1]   EVALUATION OF SECONDARY STRUCTURE OF PROTEINS FROM UV CIRCULAR-DICHROISM SPECTRA USING AN UNSUPERVISED LEARNING NEURAL-NETWORK [J].
ANDRADE, MA ;
CHACON, P ;
MERELO, JJ ;
MORAN, F .
PROTEIN ENGINEERING, 1993, 6 (04) :383-390
[2]   Lifetime imaging of a fluorescent protein sensor reveals surprising stability of ER thiol redox [J].
Avezov, Edward ;
Cross, Benedict C. S. ;
Schierle, Gabriele S. Kaminski ;
Winters, Mikael ;
Harding, Heather P. ;
Melo, Eduardo Pinho ;
Kaminski, Clemens F. ;
Ron, David .
JOURNAL OF CELL BIOLOGY, 2013, 201 (02) :337-349
[3]   Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling [J].
Bagur, Rafaela ;
Hajnoczky, Gyorgy .
MOLECULAR CELL, 2017, 66 (06) :780-788
[4]   The versatility and universality of calcium signalling [J].
Berridge, MJ ;
Lipp, P ;
Bootman, MD .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2000, 1 (01) :11-21
[5]   Physical and Functional Cross Talk Between Endo-Sarcoplasmic Reticulum and Mitochondria in Skeletal Muscle [J].
Boncompagni, Simona ;
Pozzer, Diego ;
Viscomi, Carlo ;
Ferreiro, Ana ;
Zito, Ester .
ANTIOXIDANTS & REDOX SIGNALING, 2020, 32 (12) :873-883
[6]   Intraluminal calcium as a primary regulator of endoplasmic reticulum function [J].
Burdakov, D ;
Petersen, OH ;
Verkhratsky, A .
CELL CALCIUM, 2005, 38 (3-4) :303-310
[7]   Regulation of Calcium Homeostasis by ER Redox: A Close-Up of the ER/Mitochondria Connection [J].
Chernorudskiy, Alexander L. ;
Zito, Ester .
JOURNAL OF MOLECULAR BIOLOGY, 2017, 429 (05) :620-632
[8]   How Are Proteins Reduced in the Endoplasmic Reticulum? [J].
Ellgaard, Lars ;
Sevier, Carolyn S. ;
Bulleid, Neil J. .
TRENDS IN BIOCHEMICAL SCIENCES, 2018, 43 (01) :32-43
[9]   Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44 [J].
Higo, T ;
Hattori, M ;
Nakamura, T ;
Natsume, T ;
Michikawa, T ;
Mikoshiba, K .
CELL, 2005, 120 (01) :85-98
[10]   ERO1-independent production of H2O2 within the endoplasmic reticulum fuels Prdx4-mediated oxidative protein folding [J].
Konno, Tasuku ;
Melo, Eduardo Pinho ;
Lopes, Carlos ;
Mehmeti, Ilir ;
Lenzen, Sigurd ;
Ron, David ;
Avezov, Edward .
JOURNAL OF CELL BIOLOGY, 2015, 211 (02) :253-259