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Genetic Polymorphism and Protein Conformational Plasticity in the Calmodulin Superfamily: Two Ways to Promote Multifunctionality

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Genetic Polymorphism and Protein Conformational Plasticity in the Calmodulin Superfamily: Two Ways to Promote Multifunctionality PERSPECTIVE Genetic polymorphism and protein conformational plasticity in the calmodulin superfamily: Two ways to promote multifunctionality Mitsuhiko Ikura†‡ and James B. Ames§ †Division of Signaling Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON, Canada M5G 2M9; and §Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, MD 20850 Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved December 2, 2005 (received for review October 31, 2005) Calcium signaling pathways control a variety of cellular events such as gene transcription, protein phosphorylation, nucleotide me- tabolism, and ion transport. These pathways often involve a large number of calcium-binding proteins collectively known as the cal- modulin or EF-hand protein superfamily. Many EF-hand proteins undergo a large conformational change upon binding to Ca2؉ and target proteins. All members of the superfamily share marked sequence homology and similar structural features required to sense Ca2؉. Despite such structural similarities, the functional diversity of EF-hand calcium-binding proteins is extraordinary. Calmodulin itself can bind >300 different proteins, and the many members of the neuronal calcium sensor and S100 protein families collectively recognize a largely different set of target proteins. Recent biochemical and structural studies of many different EF-hand proteins highlight remarkable similarities and variations in conformational responses to the common ligand Ca2؉ and their respective cellular targets. In this review, we examine the essence of molecular recognition activities and the mechanisms by which calmodulin super- .family proteins control a wide variety of Ca2؉ signaling processes he Ca2ϩ ion is a highly versatile by stimulating or suppressing different interhelical loop region contains several intracellular signal regulating intracellular signaling pathways (5–7). amino acids essential to the coordina- ϩ many different cellular func- The calmodulin superfamily is a major tion of a single Ca2 ion. Typically, a ϩ tions, including fertilization, cell class of Ca2 sensor proteins, which col- pair of EF-hand motifs in tandem array T lectively play a crucial role in various cel- constitutes a stable structural unit, to- cycle, apoptosis, muscle contraction, vi- sion, and memory (1). In eukaryotic lular signaling cascades through regulation gether generating cooperativity in the 2ϩ 2ϩ cells, cytoplasmic Ca2ϩ entry and out- of numerous target proteins in a Ca - binding of Ca ions (62, 63). Many EF- flow are governed by two sources: intra- dependent manner (Table 1). It has been hand proteins, such as calmodulin and cellular stores such as the endoplasmic reported that there are nearly 600 mem- members of the NCS family, consist of ϩ bers in this superfamily (60), all of which reticulum and extracellular Ca2 that four EF-hand motifs. This results in two contain one or more Ca2ϩ binding motifs enters the cell through various trans- globular structural units in a single pro- known as the EF-hand, first identified in tein. We will discuss the importance of porters on the plasma membrane (2). parvalbumin by Kretsinger and coworkers this feature to the multifunctionality of Ca2ϩ entry into the cytoplasm is tightly (7). Calmodulin contains four EF-hand these proteins. The S100 family, on the regulated by a variety of components of motifs, with highly conserved amino acid 2ϩ other hand, consists of only one globular the Ca signaling toolkit, which were sequences in all eukaryotes. In fact, this structural unit comprised of two EF- elegantly summarized by Berridge et al. sequence is ranked fifth in an amino acid hand motifs. However, members of this 2ϩ (3). The Ca flux machinery, consisting conservation contest in proteomes after family all form a stable homo- or het- of ion channels, pumps, and exchangers, the histones H4 and H3, actin B, and erodimer, which contains four EF-hand gives rise to highly localized and tran- ubiquitin (61). In contrast, the troponin C motifs in a single structural entity. ϩ sient Ca2 signals that are, in turn, family, which also contains four EF-hand The direct interaction with Ca2ϩ en- transduced by calcium-binding proteins motifs, has two isoforms in the human ables these Ca2ϩ sensor proteins to acting on various enzymes and down- (skeletal and cardiac muscles) and many change their conformation from the in- stream effector proteins. isoforms in invertebrates, all diverse in active state (P) to the intermediate state A central question in the field of amino acid sequence (6). Similarly, the (Ca2ϩ-P*), which is a prerequisite to the Ca2ϩ signaling is how different Ca2ϩ neuronal calcium sensor (NCS) and S100 formation of an active conformation in ϩ signaling systems control so many diver- proteins are diverse in sequence and func- complex with a target (Ca2 -P**-E*) gent cellular processes (3)? Such control tion. Recent advances in the structural required to transform the target protein and biochemical understanding of these from its inactive state (E) to the active is achieved at both the cellular and mo- 2ϩ lecular level. The spatial and temporal Ca sensor proteins unveiled two emerg- state (E*) 2ϩ ing themes that explain the vast multifunc- variation of Ca signals, known as ϩ 2ϩ ϩ 2ϩ tionality of the calmodulin superfamily. Ca E Ca waves, spikes, and puffs, are re- ϩ ϩ These molecular themes are genetic poly- P 9|=Ca2 -P*9|=Ca2 -P**-E*. sponsible for generating diverse output morphism and protein conformational required for different physiological con- plasticity, and are likely to be relevant to ditions (4). Also, cell-specific expression other protein superfamilies with diverse of a unique set of components from the functions. Conflict of interest statement: No conflicts declared. 2ϩ Ca signaling toolkit (3) is required for Abbreviations: KChIP, Kϩ channel-interacting protein; NCS, 2؉ generating cell-specific responses to EF-Hand as a Building Block of Ca neuronal calcium sensor. 2ϩ Ca signals. At the molecular level, a Sensor Proteins ‡To whom correspondence should be addressed. E-mail: ϩ variety of Ca2 sensor proteins provide The EF-hand motif consists of a simple [email protected]. totally different physiological responses helix-loop-helix architecture in which the © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0508640103 PNAS ͉ January 31, 2006 ͉ vol. 103 ͉ no. 5 ͉ 1159–1164 Downloaded by guest on September 29, 2021 Table 1. EF-hand Ca2؉-binding proteins and their functional target proteins (35, 36) and hippocalcin (74). Frequenin EF-hand protein Functional targets also is expressed in invertebrates, includ- ing flies (73), worms (75) and yeast (29, Calmodulin Myosin light chain kinases (8) 76). Yeast and mammalian frequenins Calmodulin-dependent protein kinases (9) bind and activate a particular phosphati- Phosphorylase kinase (10) dylinositol 4-OH kinase isoform (Pik1 Myristoylated protein kinase C substrates (11) G protein-coupled receptor kinases (GRKs) (12) gene in yeast) (29, 77) required for vesicu- Calcineurin (13) lar trafficking in the late secretory path- Adenylate cyclases (14) way (78). Mammalian frequenin (NCS-1) 2ϩ Glutamate decarboxylase (15) also regulates voltage-gated Ca channels ϩ Nitric oxide synthases (16) (31) and K channels (30). The KChIP Phosphodiesterases (17, 18) proteins regulate the gating kinetics of Plasma membrane Ca2ϩ ATPase pump (19) Shaker Kϩ channels (34). DREAM͞calse- Cyclic-nucleotide gated ion channels (20) nilin binds to specific DNA sequence ele- SK channels (21) 2ϩ ments in the prodynorphin and c-fos Voltage-gated Ca channels (22) genes (35) and serves as a transcriptional Inositol 1,4,5-trisphosphate receptors (23) Ryanodine receptors (24) repressor for pain modulation (79, 80). Troponin C Hence, the physiological functions of Skeletal (100%) Skeletal muscle Troponin I (25) the NCS proteins are highly diverse and Cardiac (65%) Cardiac muscle Troponin I (26, 27) nonoverlapping. Invertebrate (37%) Invertebrate Troponin I (28) The S100 proteins also have diverse NCS family physiological functions involved in regulat- ϩ 2ϩ Frequenin (100%) PI4-kinase (29), K channels (30), Ca channels (31) ing cell cycle control, transcription, and ␦ Neurocalcin- (55%) Nicotinic acetylcholine receptors (32) secretion (Table 1). S100A1 controls car- Recoverin (43%) Rhodopsin kinase (33) diac contractility and is associated with a KChIP1–4 (40%) Shaker channels (34) DREAM͞calensilin Dynorphin DRE (35), presenilin (36) number of cardiomyopathies (81). S100A2 GCAPs (35%) Retinal guanylate cyclases (retGCs) (37) is localized to the nucleus where it regu- Calcineurin B (32%) Calcineurin A-subunit (38) lates transcription of various genes and CIB (24%) Integrin (39), presenilins (40) acts as a tumor suppressor in breast can- CaBP1 (22%) Inositol 1,4,5-trisphosphate receptors (41), voltage-gated Ca2ϩ channels (42) cer cells (82). In contrast, S100A4 (83) S100 family and S100A6 (47) are both tumor promot- S100A1 (100%) Titin (43), SERCA2a (44), ryanodine receptor (45) ers. S100A7 acts extracellularly and is S100A4 (53%) Methionine aminopeptidase 2 (46) implicated in epidermal inflammatory S100A6 (48%) Ubiquitin ligase (47) diseases such as psoriasis (84). The S100A10 (47%) Annexin II (48) ͞ S100A11 (43%) Annexin I (49) S100A8 A9 heterodimer acts extracellu- S100A12 (40%)
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