Information Transfer in the Penta-EF-hand Protein Sorcin Does Not Operate via the Canonical Structural/Functional Pairing

Mella, Manuela; Colotti, Gianni; Zamparelli, Carlotta; Verzili, Daniela; Ilari, Andrea; Chiancone, Emilia

doi:10.1074/jbc.m213276200

Cited by 39 publications

(44 citation statements)

References 40 publications

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“…Structural and genetic studies have suggested causality between a naturally occurring sorcin mutant (F112L) and inherited hypertension and hypertrophic cardiomyopathy (552,595,912). Currently, the sorcin F112L mutant has not been studied using acute gene transfer, but a transgenic mouse model with 20-fold overexpression of this mutation has a dilated phenotype (131).…”

Section: Sorcinmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Section: Sorcinmentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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“…The effects of the mutations on the interaction parameters were assessed in surface plasmon resonance experiments, while those on function were determined by means of NCX current measurements. Specifically, the C-terminal, sorcin Ca 2+ -binding domain (SCBD) was employed to establish whether this domain is the interacting one [4,32]; the E124A mutant was used to gain information on the Ca 2+ -dependence of the interaction since this variant is unable to bind Ca 2+ at physiological concentrations due to substitution of the bidentate Ca 2+ ligand at the EF3 hand [33]; the W99G and W105G variants were utilized as selective probes of the local structural perturbations introduced by substitution of the two tryptophan residues located at the beginning and end of the D helix [34].…”

Section: Introductionmentioning

confidence: 99%

Activation of the cardiac Na+–Ca2+ exchanger by sorcin via the interaction of the respective Ca2+-binding domains

Zamparelli

Macquaide

Colotti

et al. 2010

Journal of Molecular and Cellular Cardiology

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Sorcin is a penta-EF-hand protein that interacts with intracellular target proteins after Ca2+ binding. The sarcolemmal Na+/Ca2+ exchanger (NCX1) may be an important sorcin target in cardiac muscle. In this study, RNAi knockdown of sorcin, purified sorcin or sorcin variants was employed in parallel measurements of: (i) NCX activity in isolated rabbit cardiomyocytes using electrophysiological techniques and (ii) sorcin binding to the NCX1 calcium binding domains (CBD1 and (iii) using surface plasmon resonance and gel overlay techniques. Sorcin is activated by Ca2+ binding to the EF3 and EF2 regions, which are connected by the D helix. To investigate the importance of this region in the interaction with NCX1, three variants were examined: W105G and W99G, mutated respectively near EF3 and EF2, and E124A that does not bind Ca2+ due to a mutation at EF3. Downregulation of sorcin decreased and supplementation with wt sorcin (3 μM) increased NCX activity in isolated cardiomyocytes. The relative stimulatory effects of the sorcin variants were: W105G > wt sorcin > Sorcin Calcium Binding Domain (SCBD) > W99G > E124A. Sorcin binding to both CBD1 and 2 was observed. In the presence of 50 µM Ca2+, the interaction with CBD1 followed the order W105G > SCBD > wt sorcin > W99G > E124A. In sorcin, the interacting surface can be mapped on the C-terminal Ca2+-binding domain in the D helix region comprising W99. The fast association/dissociation rates that characterize the interaction of sorcin with CBD1 and 2 may permit complex formation/dissociation during an excitation/contraction cycle.

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“…Crystallographic analysis of wild‐type (WT) sorcin suggests that F112 is within a D helix and participates in transmission of Ca 2+ ‐mediated conformational changes. Consequently, replacement of this residue with leucine may impinge on the dynamic, Ca 2+ ‐dependent translocation of sorcin from soluble to cellular membrane sites (14, 16, 17). Indeed, preliminary in vitro studies in planar lipid bilayers suggest that, unlike WT sorcin, the L112 variant does not diminish RyR2 open probability (18).…”

mentioning

confidence: 99%

Expression of a sorcin missense mutation in the heart modulates excitation‐contraction coupling

et al. 2006

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Sorcin is a Ca2+ binding protein implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. Structural and human genetic studies suggest that a naturally occurring sequence variant encoding L112-sorcin disrupts an E-F hand Ca2+ binding domain and may be responsible for a heritable form of hypertension and hypertrophic heart disease. We generated transgenic mice overexpressing L112-sorcin in the heart and characterized the effects on Ca2+ regulation and cardiac function both in vivo and in dissociated cardiomyocytes. Hearts of sorcin(F112L) transgenic mice were mildly dilated but ventricular function was preserved and systemic blood pressure was normal. Sorcin(F112L) myocytes were smaller than control cells and displayed complex alterations in Ca2+ regulation and contractility, including a slowed inactivation of L-type Ca2+ current, enhanced Ca2+ spark width, duration, and frequency, and increased Na+-Ca2+ exchange activity. In contrast, mice with cardiac-specific overexpression of wild-type sorcin displayed directionally opposite effects on L-type Ca2+ channel function and Ca2+ spark behavior. These data further define the role of sorcin in cardiac excitation-contraction coupling and highlight its negative regulation of SR calcium release. Our results also suggest that additional factors may be responsible for the development of cardiac hypertrophy and hypertension in humans expressing the L112-sorcin sequence variant.

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Information Transfer in the Penta-EF-hand Protein Sorcin Does Not Operate via the Canonical Structural/Functional Pairing

Cited by 39 publications

References 40 publications

Designing Heart Performance by Gene Transfer

Designing Heart Performance by Gene Transfer

Activation of the cardiac Na+–Ca2+ exchanger by sorcin via the interaction of the respective Ca2+-binding domains

Expression of a sorcin missense mutation in the heart modulates excitation‐contraction coupling

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