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Biomolecules
Special Issues
S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology
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S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 20941

Special Issue Editors

Prof. Wiesława Leśniak

E-Mail Website
Guest Editor
Nencki Institute of Experimental Biology, Warsaw, Poland
Interests: cell/molecular biology; biochemistry; cell proteostasis; cancer; neurodegeneration; gene/protein expression; epigenetics
Prof. Dr. Anna Filipek

E-Mail Website
Guest Editor
Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Warsaw, Poland
Interests: cell/molecular biology; protein biochemistry; protein-protein interaction; cell proteostasis; neurodegeneration; gene/protein expression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The S100 protein family, which assembles small homo- or heterodimeric calcium binding proteins with two EF-hands, emerged in 1965 with the discovery of its founder member, and grew to include more than 20 proteins. The special trait of S100 proteins is that, in spite of their close sequence and structural similarity oweing to a common ancestor gene, they exhibit an amazing versatility of interactions and biological functions. This versatility is mainly due to the existing variations in the amino acid sequence, especially in the C-terminal fragment of variable length, differences in Ca2+ -binding characteristics, homo- versus heterodimer formation, and cell-specific expression. All these factors contribute to the uniqueness of each S100 protein and ensure that their multiple functions, exerted both intra- and extracellularly, are not redundant. Moreover, because of their functional specificity, the pattern of changes in S100 protein expression observed in various pathological states is usually typical for a given disease and may facilitate proper diagnosis.

The Special Issue of Biomolecules, entitled “S100 proteins - intracellular and extracellular function in norm and pathology”, intends to provide a broad platform to show the many aspects of the biology of S100 proteins. We encourage and invite you to publish your recent research results and/or reviews concerning this topic in this Special Issue of Biomolecules.

Prof. Wiesława Leśniak
Prof. Anna Filipek
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ca2+, Ca2+-binding proteins
  • EF-hand
  • S100 proteins
  • intracellular and extracellular targets of S100 proteins
  • membrane receptors of S100 proteins
  • S100 proteins as biomarkers
  • involvement of S100 proteins in signaling pathways
  • the intracellular and extracellular role of S100 proteins in proliferation, tumorigenesis, tissue repair/regeneration, migration, invasiveness, cytoskeleton organization, neurodegeneration

Published Papers (7 papers)

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Research

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21 pages, 3547 KiB  
Article
The Role of the C-Terminal Lysine of S100P in S100P-Induced Cell Migration and Metastasis
by Thamir M. Ismail, Stephane R. Gross, Tara Lancaster, Philip S. Rudland and Roger Barraclough
Biomolecules 2021, 11(10), 1471; https://doi.org/10.3390/biom11101471 - 6 Oct 2021
Cited by 2 | Viewed by 2190
Abstract
S100P protein is a potent inducer of metastasis in a model system, and its presence in cancer cells of patients is strongly associated with their reduced survival times. A well-established Furth Wistar rat metastasis model system, methods for measuring cell migration, and specific [...] Read more.
S100P protein is a potent inducer of metastasis in a model system, and its presence in cancer cells of patients is strongly associated with their reduced survival times. A well-established Furth Wistar rat metastasis model system, methods for measuring cell migration, and specific inhibitors were used to study pathways of motility-driven metastasis. Cells expressing C-terminal mutant S100P proteins display markedly-reduced S100P-driven metastasis in vivo and cell migration in vitro. These cells fail to display the low focal adhesion numbers observed in cells expressing wild-type S100P, and the mutant S100P proteins exhibit reduced biochemical interaction with non-muscle myosin heavy chain isoform IIA in vitro. Extracellular inhibitors of the S100P-dependent plasminogen activation pathway reduce, but only in part, wild-type S100P-dependent cell migration; they are without effect on S100P-negative cells or cells expressing C-terminal mutant S100P proteins and have no effect on the numbers of focal adhesions. Recombinant wild-type S100P protein, added extracellularly to S100P-negative cells, stimulates cell migration, which is abolished by these inhibitors. The results identify at least two S100P-dependent pathways of migration, one cell surface and the other intracellularly-linked, and identify its C-terminal lysine as a target for inhibiting multiple migration-promoting activities of S100P protein and S100P-driven metastasis. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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16 pages, 2035 KiB  
Article
Differential Regulation of Circulating Soluble Receptor for Advanced Glycation End Products (sRAGEs) and Its Ligands S100A8/A9 Four Weeks Post an Exercise Intervention in a Cohort of Young Army Recruits
by Ioannis-Alexandros Drosatos, James N. Tsoporis, Shehla Izhar, Sahil Gupta, George Tsirebolos, Eleftherios Sakadakis, Andreas S. Triantafyllis, Angelos Rigopoulos, Dimitrios Rigopoulos, Loukianos S. Rallidis, Ioannis Rizos and Thomas G. Parker
Biomolecules 2021, 11(9), 1354; https://doi.org/10.3390/biom11091354 - 13 Sep 2021
Cited by 7 | Viewed by 2017
Abstract
Apart from its beneficial effects on cardiovascular risk factors, an anti-inflammatory effect of exercise is strongly implicated. Yet, data regarding the effect of an exercise intervention on healthy individuals are limited and contradictory. The present study aimed to investigate the effects of a [...] Read more.
Apart from its beneficial effects on cardiovascular risk factors, an anti-inflammatory effect of exercise is strongly implicated. Yet, data regarding the effect of an exercise intervention on healthy individuals are limited and contradictory. The present study aimed to investigate the effects of a physical activity intervention on the soluble form of the receptor for advanced glycation end products (sRAGEs) and its ligands S100A8/A9. A total of 332 young army recruits volunteered and 169 completed the study. The participants underwent the standard basic training of Greek army recruits. IL-6, IL-1β, S100A8/A9, and sRAGEs were measured at the beginning and at the end of the training period. Primary rodent adult aortic smooth muscle cells (ASMCs) were analyzed for responsiveness to direct stimulation with S100A8/A9 alone or in combination with sRAGEs. At the end of the training period, we observed a statistically significant reduction in S100A8/A9 (630.98 vs. 472.12 ng/mL, p = 0.001), IL-1β (9.39 [3.8, 44.14] vs. 5.03 [2.44, 27.3] vs. pg/mL, p = 0.001), and sRAGEs (398.38 vs. 220.1 pg/mL, p = 0.001). IL-6 values did not change significantly after exercise. S100A8/A9 reduction was positively correlated with body weight (r = 0.236 [0.095, 0.370], p = 0.002) and BMI (r = 0.221 [0.092, 0.346], p = 0.004). Direct stimulation of ASMCs with S100A8/A9 increased the expression of IL-6, IL-1β, and TNF-α and, in the presence of sRAGEs, demonstrated a dose-dependent inhibition. A 4-week military training resulted in significant reduction in the pro-inflammatory cytokines IL-1β and S100A8/A9 complex. The observed reduction in sRAGEs may possibly reflect diminished RAGE axis activation. Altogether, our findings support the anti-inflammatory properties of physical activity. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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9 pages, 1074 KiB  
Communication
Regulation of S100A10 Gene Expression
by Aleksandra Głowacka, Paweł Bieganowski, Ewelina Jurewicz, Wiesława Leśniak, Tomasz Wilanowski and Anna Filipek
Biomolecules 2021, 11(7), 974; https://doi.org/10.3390/biom11070974 - 2 Jul 2021
Cited by 4 | Viewed by 2568
Abstract
S100A10, a member of the S100 family of Ca2+-binding proteins, is a widely distributed protein involved in many cellular and extracellular processes. The best recognized role of S100A10 is the regulation, via interaction with annexin A2, of plasminogen conversion to plasmin. [...] Read more.
S100A10, a member of the S100 family of Ca2+-binding proteins, is a widely distributed protein involved in many cellular and extracellular processes. The best recognized role of S100A10 is the regulation, via interaction with annexin A2, of plasminogen conversion to plasmin. Plasmin, together with other proteases, induces degradation of the extracellular matrix (ECM), which is an important step in tumor progression. Additionally, S100A10 interacts with 5-hydroxytryptamine 1B (5-HT1B) receptor, which influences neurotransmitter binding and, through that, depressive symptoms. Taking this into account, it is evident that S100A10 expression in the cell should be under strict control. In this work, we summarize available literature data concerning the physiological stimuli and transcription factors that influence S100A10 expression. We also present our original results showing for the first time regulation of S100A10 expression by grainyhead-like 2 transcription factor (GRHL2). By applying in silico analysis, we have found two highly conserved GRHL2 binding sites in the 1st intron of the gene encoding S100A10 protein. Using chromatin immunoprecipitation (ChIP) and luciferase assays, we have shown that GRHL2 directly binds to these sites and that this DNA region can affect transcription of S100A10. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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15 pages, 4115 KiB  
Article
S100P Interacts with p53 while Pentamidine Inhibits This Interaction
by Revansiddha H. Katte, Deepu Dowarha, Ruey-Hwang Chou and Chin Yu
Biomolecules 2021, 11(5), 634; https://doi.org/10.3390/biom11050634 - 24 Apr 2021
Cited by 1 | Viewed by 2229
Abstract
S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may involve binding-induced inactivation of p53. We used 1H-15N HSQC experiments and molecular modeling to study the [...] Read more.
S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may involve binding-induced inactivation of p53. We used 1H-15N HSQC experiments and molecular modeling to study the molecular interactions between S100P and p53 in the presence and absence of pentamidine. Our experimental analysis indicates that the S100P-53 complex formation is successfully disrupted by pentamidine, since S100P shares the same binding site for p53 and pentamidine. In addition, we showed that pentamidine treatment of ZR-75-1 breast cancer cells resulted in reduced proliferation and increased p53 and p21 protein levels, indicating that pentamidine is an effective antagonist that interferes with the S100P-p53 interaction, leading to re-activation of the p53-21 pathway and inhibition of cancer cell proliferation. Collectively, our findings suggest that blocking the association between S100P and p53 by pentamidine will prevent cancer progression and, therefore, provide a new avenue for cancer therapy by targeting the S100P-p53 interaction. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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11 pages, 1919 KiB  
Communication
Identification and Biochemical Characterization of High Mobility Group Protein 20A as a Novel Ca2+/S100A6 Target
by Maho Yamamoto, Rina Kondo, Haruka Hozumi, Seita Doi, Miwako Denda, Masaki Magari, Naoki Kanayama, Naoya Hatano, Ryo Morishita and Hiroshi Tokumitsu
Biomolecules 2021, 11(4), 510; https://doi.org/10.3390/biom11040510 - 30 Mar 2021
Cited by 3 | Viewed by 1996
Abstract
During screening of protein-protein interactions, using human protein arrays carrying 19,676 recombinant glutathione s-transferase (GST)-fused human proteins, we identified the high-mobility protein group 20A (HMG20A) as a novel S100A6 binding partner. We confirmed the Ca2+-dependent interaction of HMG20A with S100A6 by [...] Read more.
During screening of protein-protein interactions, using human protein arrays carrying 19,676 recombinant glutathione s-transferase (GST)-fused human proteins, we identified the high-mobility protein group 20A (HMG20A) as a novel S100A6 binding partner. We confirmed the Ca2+-dependent interaction of HMG20A with S100A6 by the protein array method, biotinylated S100A6 overlay, and GST-pulldown assay in vitro and in transfected COS-7 cells. Co-immunoprecipitation of S100A6 with HMG20A from HeLa cells in a Ca2+-dependent manner revealed the physiological relevance of the S100A6/HMG20A interaction. In addition, HMG20A has the ability to interact with S100A1, S100A2, and S100B in a Ca2+-dependent manner, but not with S100A4, A11, A12, and calmodulin. S100A6 binding experiments using various HMG20A mutants revealed that Ca2+/S100A6 interacts with the C-terminal region (residues 311–342) of HMG20A with stoichiometric binding (HMG20A:S100A6 dimer = 1:1). This was confirmed by the fact that a GST-HMG20A mutant lacking the S100A6 binding region (residues 311–347, HMG20A-ΔC) failed to interact with endogenous S100A6 in transfected COS-7 cells, unlike wild-type HMG20A. Taken together, these results identify, for the first time, HMG20A as a target of Ca2+/S100 proteins, and may suggest a novel linkage between Ca2+/S100 protein signaling and HMG20A function, including in the regulation of neural differentiation. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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Review

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14 pages, 3464 KiB  
Review
A Structural Perspective on Calprotectin as a Ligand of Receptors Mediating Inflammation and Potential Drug Target
by Velia Garcia, Yasiru Randika Perera and Walter Jacob Chazin
Biomolecules 2022, 12(4), 519; https://doi.org/10.3390/biom12040519 - 30 Mar 2022
Cited by 9 | Viewed by 4586
Abstract
Calprotectin, a heterodimer of S100A8 and S100A9 EF-hand calcium-binding proteins, is an integral part of the innate immune response. Calprotectin (CP) serves as a ligand for several pattern recognition cell surface receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor [...] Read more.
Calprotectin, a heterodimer of S100A8 and S100A9 EF-hand calcium-binding proteins, is an integral part of the innate immune response. Calprotectin (CP) serves as a ligand for several pattern recognition cell surface receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and cluster of differentiation 33 (CD33). The receptors initiate kinase signaling cascades that activate inflammation through the NF-kB pathway. Receptor activation by CP leads to upregulation of both receptor and ligand, a positive feedback loop associated with specific chronic inflammatory syndromes. Hence, CP and its two constituent homodimers have been viewed as potential targets to suppress certain chronic inflammation pathologies. A variety of inhibitors of CP and other S100 proteins have been investigated for more than 30 years, but no candidates have advanced significantly into clinical trials. Here, current knowledge of the interactions of CP with its receptors is reviewed along with recent progress towards the development of CP-directed chemotherapeutics. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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18 pages, 1643 KiB  
Review
The Annexin A2/S100A10 Complex: The Mutualistic Symbiosis of Two Distinct Proteins
by Alamelu Bharadwaj, Emma Kempster and David Morton Waisman
Biomolecules 2021, 11(12), 1849; https://doi.org/10.3390/biom11121849 - 9 Dec 2021
Cited by 23 | Viewed by 4117
Abstract
Mutualistic symbiosis refers to the symbiotic relationship between individuals of different species in which both individuals benefit from the association. S100A10, a member of the S100 family of Ca2+-binding proteins, exists as a tight dimer and binds two annexin A2 molecules. [...] Read more.
Mutualistic symbiosis refers to the symbiotic relationship between individuals of different species in which both individuals benefit from the association. S100A10, a member of the S100 family of Ca2+-binding proteins, exists as a tight dimer and binds two annexin A2 molecules. This association forms the annexin A2/S100A10 complex known as AIIt, and modifies the distinct functions of both proteins. Annexin A2 is a Ca2+-binding protein that binds F-actin, phospholipid, RNA, and specific polysaccharides such as heparin. S100A10 does not bind Ca2+, but binds tPA, plasminogen, certain plasma membrane ion channels, neurotransmitter receptors, and the structural scaffold protein, AHNAK. S100A10 relies on annexin A2 for its intracellular survival: in the absence of annexin A2, it is rapidly destroyed by ubiquitin-dependent and independent proteasomal degradation. Annexin A2 requires S100A10 to increase its affinity for Ca2+, facilitating its participation in Ca2+-dependent processes such as membrane binding. S100A10 binds tissue plasminogen activator and plasminogen, and promotes plasminogen activation to plasmin, which is a process stimulated by annexin A2. In contrast, annexin A2 acts as a plasmin reductase and facilitates the autoproteolytic destruction of plasmin. This review examines the relationship between annexin A2 and S100A10, and how their mutualistic symbiosis affects the function of both proteins. Full article
(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)
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