S100 proteins in health and disease (original) (raw)
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Functional roles of S100 proteins, calcium-binding proteins of the EF-hand type
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1999
A multigenic family of Ca 2 -binding proteins of the EF-hand type known as S100 comprises 19 members that are differentially expressed in a large number of cell types. Members of this protein family have been implicated in the Ca 2dependent (and, in some cases, Zn 2 -or Cu 2 -dependent) regulation of a variety of intracellular activities such as protein phosphorylation, enzyme activities, cell proliferation (including neoplastic transformation) and differentiation, the dynamics of cytoskeleton constituents, the structural organization of membranes, intracellular Ca 2 homeostasis, inflammation, and in protection from oxidative cell damage. Some S100 members are released or secreted into the extracellular space and exert trophic or toxic effects depending on their concentration, act as chemoattractants for leukocytes, modulate cell proliferation, or regulate macrophage activation. Structural data suggest that many S100 members exist within cells as dimers in which the two monomers are related by a two-fold axis of rotation and that Ca 2 binding induces in individual monomers the exposure of a binding surface with which S100 dimers are believed to interact with their target proteins. Thus, any S100 dimer is suggested to expose two binding surfaces on opposite sides, which renders homodimeric S100 proteins ideal for crossbridging two homologous or heterologous target proteins. Although in some cases different S100 proteins share their target proteins, in most cases a high degree of target specificity has been described, suggesting that individual S100 members might be implicated in the regulation of specific activities. On the other hand, the relatively large number of target proteins identified for a single S100 protein might depend on the specific role played by the individual regions that in an S100 molecule contribute to the formation of the binding surface. The pleiotropic roles played by S100 members, the identification of S100 target proteins, the analysis of functional correlates of S100-target protein interactions, and the elucidation of the threedimensional structure of some S100 members have greatly increased the interest in S100 proteins and our knowledge of S100 protein biology in the last few years. S100 proteins probably are an example of calcium-modulated, regulatory proteins that intervene in the fine tuning of a relatively large number of specific intracellular and (in the case of some members) extracellular activities. Systems, including knock-out animal models, should be now used with the aim of defining the correspondence between the in vitro regulatory role(s) attributed to individual members of this protein family and the in vivo function(s) of each S100 protein. ß 0167-4889 / 99 / $^see front matter ß 1999 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 -4 8 8 9 ( 9 9 ) 0 0 0 5 8 -0 * Pro¢laggrin Keratins [24,26] Regulates lateral association of keratin intermediate ¢laments [24,26] Trychohyalin Keratins [25] Regulates lateral association of keratin intermediate ¢laments [25] Repetin Keratins [27] Regulates lateral association of keratin intermediate ¢laments [27]
Perspectives in S-100 protein biology
Cell Calcium, 1991
The S-100 protein family constitutes a subgroup of Ca2"-binding proteins of the EF-hand type comprising three dimeric isofotms, S-1OOao , S-1OOa and S-IOOb, pius a number of structurally related proteins displaying 2845% homology with S-100 subunits. S-100 protein was discovered in 1965; yet, its biological functions have not been fully elucidated. The present report will review the putative biological roles of S-100 protein.
The International Journal of Biochemistry & Cell Biology, 2001
S100 is a multigenic family of non-ubiquitous Ca 2 + -modulated proteins of the EF-hand type expressed in vertebrates exclusively and implicated in intracellular and extracellular regulatory activities. Within cells, most of S100 members exist in the form of antiparallely packed homodimers (in some cases heterodimers), capable of functionally crossbridging two homologous or heterologous target proteins in a Ca 2 + -dependent (and, in some instances, Ca 2 + -independent) manner. S100 oligomers can also form, under the non-reducing conditions found in the extracellular space and/or within cells upon changes in the cell redox status. Within cells, S100 proteins have been implicated in the regulation of protein phosphorylation, some enzyme activities, the dynamics of cytoskeleton components, transcription factors, Ca 2 + homeostasis, and cell proliferation and differentiation. Certain S100 members are released into the extracellular space by an unknown mechanism. Extracellular S100 proteins stimulate neuronal survival and/or differentiation and astrocyte proliferation, cause neuronal death via apoptosis, and stimulate (in some cases) or inhibit (in other cases) the activity of inflammatory cells. A cell surface receptor, RAGE, has been identified on inflammatory cells and neurons for S100A12 and S100B, which transduces S100A12 and S100B effects. It is not known whether RAGE is a universal S100 receptor, S100 members interact with other cell surface receptors, or S100 protein interaction with other extracellular factors specifies the biological effects of a given S100 protein on a target cell. The variety of intracellular target proteins of S100 proteins and, in some cases, of a single S100 protein, and the cell specificity of expression of certain S100 members suggest that these proteins might have a role in the fine regulation of effector proteins and/or specific steps of signaling pathways/cellular functions. Future analyses should discriminate between functionally relevant S100 interactions with target proteins and in vitro observations devoid of physiological importance.
Probing the S100 protein family through genomic and functional analysis
Genomics, 2004
The EF-hand superfamily of calcium binding proteins includes the S100, calcium binding protein, and troponin subfamilies. This study represents a genome, structure, and expression analysis of the S100 protein family, in mouse, human, and rat. We confirm the high level of conservation between mammalian sequences but show that four members, including S100A12, are present only in the human genome. We describe three new members of the S100 family in the three species and their locations within the S100 genomic clusters and propose a revised nomenclature and phylogenetic relationship between members of the EF-hand superfamily. Two of the three new genes were induced in bone-marrow-derived macrophages activated with bacterial lipopolysaccharide, suggesting a role in inflammation. Normal human and murine tissue distribution profiles indicate that some members of the family are expressed in a specific manner, whereas others are more ubiquitous. Structure-function analysis of the chemotactic properties of murine S100A8 and human S100A12, particularly within the active hinge domain, suggests that the human protein is the functional homolog of the murine protein. Strong similarities between the promoter regions of human S100A12 and murine S100A8 support this possibility. This study provides insights into the possible processes of evolution of the EF-hand protein superfamily. Evolution of the S100 proteins appears to have occurred in a modular fashion, also seen in other protein families such as the C2H2-type zinc-finger family.
Cell Calcium, 1986
S-100 is a group of closely related, small, acidic Ca2+-binding proteins (S-lOOa0, S-100a and S-lOOb, which are ata, dp, and pp in composition, respectively). S-100 is structurally related to calmodulin and other Ca2+-binding proteins. S-100 is abundant in the brain and is contained in well defined cell types of both neuroectodermal and non-neuroectodermal origin, as well as in their neoplastic counterparts. In the mammalian brain, S-100a and S-100b are confined to glial cells, while S-100aO is neuronal in localization. Single S-100 isoforms bind Ca2+ with nearly the same affinity. Ei+ antagonizes the binding of Ca2+ to high affinity sites on S-100. S-100 binds Zn2+ with high affinity. S-100 is found in a soluble and a membrane-bound form and has the ability to interact with artificial and natural membranes. S-100 has no enzymic activity. S-100 has been involved in several activities including memory processes, regulation of diffusion of mono valent cations across membranes, modulation of the physical state of membranes, regulation of the phosphorylation of several proteins, control of the assembly-disassembly of microtubules. Some of these effects are strictly Ca2+dependent, while other are not. S-100 is being secreted or released to the extracellular space. In some cases, this event is hormonally regulated. Several S-100 binding proteins are being described.
S100B protein in tissue development, repair and regeneration
World Journal of Biological Chemistry, 2013
The Ca 2+ -binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular regulatory activities. As an intracellular regulator, S100B is involved in the regulation of energy metabolism, transcription, protein phosphorylation, cell proliferation, survival, differentiation and motility, and Ca 2+ homeostasis, by interacting with a wide array of proteins (i.e. , enzymes, enzyme substrates, cytoskeletal subunits, scaffold/adaptor proteins, transcription factors, ubiquitin E3 ligases, ion channels) in a restricted number of cell types. As an extracellular signal, S100B engages the pattern recognition receptor, receptor for advanced glycation end-products (RAGE), on immune cells as well as on neuronal, astrocytic and microglial cells, vascular smooth muscle cells, skeletal myoblasts and cardiomyocytes. However, RAGE may not be the sole receptor activated by S100B, the protein being able to enhance bFGF-FGFR1 signaling by interacting with FGFR1-bound bFGF in particular cell types. Moreover, extracellular effects of S100B vary depending on its local concentration. Increasing evidence suggests that at the concentration found in extracellular fluids in normal physiological conditions and locally upon acute tissue injury, which is up to a few nM levels, S100B exerts trophic effects in the central and peripheral nervous system and in skeletal muscle tissue thus participating in tissue homeostasis. The present commentary summarizes results implicating intracellular and extracellular S100B in tissue development, repair and regeneration. S100B belongs to a multigenic family of small (mol. wt. between 9 kDa and 14 kDa) Ca 2+ -binding proteins of the EF-hand type comprising more than 20 members exclusively expressed in vertebrates [1,2] . Like other members of this protein family, S100B is expressed in a cell-specific
Identity Between Cytoplasmic and Membrane-Bound S-100 Proteins Purified from Bovine and Rat Brain
Journal of Neurochemistry, 1986
Cytoplasmic and membrane-bound S-100 proteins were purified to homogeneity from bovine and rat brain. cytoplasmic and membrane-bound S-100 from single species are identical by immunological, electrophoretic, spectrophotometric, and functional criteria. Cytoplasmic and membrane-bound S-100 from bovine brain consists of nearly equal amounts of S-100a and S-100b, whereas cytoplasmic and membrane-bound S-100 from rat brain consists mostly of S-100b. The functional role of membrane-bound S-100 remains to be elucidated. Key Words: Cytoplasmic S-100-Membranebound S-100-Purification-Identity. Donato R. et al.
The Calcium-Dependent Interaction of S100B with Its Protein Targets
Cardiovascular psychiatry and neurology, 2010
S100B is a calcium signaling protein that is a member of the S100 protein family. An important feature of S100B and most other S100 proteins (S100s) is that they often bind Ca(2+) ions relatively weakly in the absence of a protein target; upon binding their target proteins, Ca(2+)-binding then increases by as much as from 200- to 400-fold. This manuscript reviews the structural basis and physiological significance of increased Ca(2+)-binding affinity in the presence of protein targets. New information regarding redundancy among family members and the structural domains that mediate the interaction of S100B, and other S100s, with their targets is also presented. It is the diversity among individual S100s, the protein targets that they interact with, and the Ca(2+) dependency of these protein-protein interactions that allow S100s to transduce changes in [Ca(2+)](intracellular) levels into spatially and temporally unique biological responses.